IMMUNOMODULATORY ONCOLYTIC ADENOVIRAL VECTORS, AND METHODS OF PRODUCTION AND USE THEREOF FOR TREATMENT OF CANCER

Abstract

Disclosed herein are compositions and methods for treating cancer in a subject. This involves administering an oncolytic virus containing a heterologous DNA sequence encoding one or more immunomodulatory and/or immunostimulatory polypeptide(s) of interest to the subject under conditions effective to enhance an anti-tumor immune response in the subject, and to treat cancer. It also relates to a method of enhancing the delivery to and distribution within a tumor mass of therapeutic viruses.

Description

FIELD

[0001] The invention described herein relates generally to the fields of immunology, virology, molecular biology, and more specifically to oncolytic adenoviruses having therapeutic applications.

BACKGROUND

[0002] Cancer is a leading cause of death in the United States and elsewhere. Depending on the type of cancer, it is typically treated with surgery, chemotherapy, and/or radiation. These treatments often fail, and it is clear that new therapies are necessary, to be used alone or in combination with current standards of care.

[0003] Originally conceived as solely tumor-lysing therapeutics, viruses that can preferentially target tumor cells for destruction are being used experimentally as vectors for the delivery of immune-stimulating cargo. The propagation of a lasting anti-tumor host immune response in combination with the destruction of tumor cells is described in, e.g., Lichty et al., 2014, Nature Reviews Cancer, 14: 559-567.

[0004] Clinical trials employing adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia as oncolytic viruses have suggested that these platforms may all be safe treatment approaches.

[0005] Adenoviruses are medium-sized (90-100 nm), non-enveloped icosahedral viruses, which have double stranded linear DNA of about 36 kilobase pairs in a protein capsid. The viral capsid has fiber structures that participate in attachment of the virus to the target cell. First, the knob domain of the fiber protein binds to the receptor of the target cell (e.g., CD46 or Coxsackie and adenovirus receptor (CAR)), secondly, the virus interacts with an integrin molecule and thirdly, the virus is endocytosed into the target cell. Next, the viral genome is transported from endosomes into the nucleus and the replication machinery of the target cell is utilized also for viral purposes.

[0006] The adenoviral genome has early (E1-E4), intermediate (IX and IVa2) and late genes (L1-L5), which are transcribed in sequential order. Early gene products affect defense mechanisms, cell cycle and cellular metabolism of the host cell. Intermediate and late genes encode structural viral proteins for production of new virions.

[0007] More than 60 different serotypes of adenoviruses have been found in humans. Serotypes are classified into six subgroups A-F and different serotypes are known to be associated with different conditions i.e. respiratory diseases, conjunctivitis and gastroenteritis. Adenovirus serotype 5 (Ad-5) is known to cause respiratory diseases and it is the most common serotype studied in the field of gene therapy. In the first Ad5 vectors E1 and/or E3 regions were deleted enabling insertion of foreign DNA to the vectors.

[0008] Furthermore, deletions of other regions as well as further mutations have provided extra properties to viral vectors. Indeed, various modifications of adenoviruses have been suggested for achieving efficient anti-tumor effects.

[0009] Adenoviral vectors mediate gene transfer at a high efficacy compared to other vector systems, and they are currently the most frequently used vectors for cancer gene therapy. A non-replicating p53 expressing adenoviral vector and a replication selective virus (H101) have received regulatory approval in China. Several attempts to achieve tumor-selective control through the insertion of tumor selective promoter elements upstream of the E1 or other adenovirus critical promoters have had variable levels of success, but ultimately were limited by "leaky" gene expression of viral proteins in non-tumor cells and by reduced ability to propagate and lyse tumor cells compared to wild-type virus infections.

SUMMARY

[0010] In a first aspect, a pharmaceutical composition is provided comprising an effective amount of a recombinant adenoviral vector comprising: a transgene insertion site located between the start site of adenoviral E1b-19K and the start site of adenoviral E1b-55K, wherein a first DNA sequence and a second DNA sequence are each inserted into the transgene insertion site; wherein the first DNA sequence encodes a polypeptide selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand, and wherein the second DNA sequence encodes a polypeptide selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand; and wherein the adenoviral vector comprises a modified adenoviral E1a regulatory sequence wherein at least one Pea3 binding site, or a functional portion thereof, of the recombinant adenoviral vector is modified or deleted.

[0011] In one embodiment, the adenoviral vector comprises an IRES element or encodes a self-cleaving 2A peptide sequence between the first DNA sequence and the second DNA sequence. In another embodiment, the vector comprises a modified E3 region. In another embodiment, the vector comprises an intact E3 region. In another embodiment, the vector comprises a third DNA sequence inserted into the E3 region, wherein the third DNA sequence encodes a polypeptide selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, or a human OX40 ligand. In one embodiment, the chimeric human IL-12 polypeptide comprises a p40 polypeptide, a p35 polypeptide, and a linker polypeptide. In another embodiment, the chimeric human IL-12 polypeptide comprises a sequence as set forth in SEQ ID NO:46.

[0012] In one embodiment, the adenoviral vector comprises a nucleic acid sequence at least 95% identical in an E3 region to vector d1327. In another embodiment, the adenoviral vector comprises a nucleic acid sequence at least 85% identical in an E3 region to vector d1327. In another embodiment, the adenoviral vector comprises a nucleic acid sequence at least 75% identical in an E3 region to vector d1327.

[0013] In one embodiment, the pharmaceutical composition is formulated for systemic administration. In another embodiment, the pharmaceutical composition is formulated for intratumoral administration.

[0014] In a second aspect is provided a pharmaceutical composition comprising an effective amount of a recombinant adenoviral vector comprising: a first transgene insertion site located between the start site of adenoviral E1b-19K and the start site of adenoviral E1b-55K; a second transgene insertion site located in adenoviral E3 region; a first DNA sequence, present in the first transgene insertion site, encoding one or a plurality of polypeptides selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand; and a second DNA sequence, present in the second transgene insertion site, encoding one or a plurality of polypeptides selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand, wherein the adenoviral vector comprises a modified adenoviral E1a regulatory sequence. In one embodiment, the pharmaceutical composition further comprises a third DNA sequence inserted into a third transgene insertion site, encoding one or a plurality of polypeptides selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand.

[0015] In another embodiment, at least one of the first DNA sequence, the second DNA sequence, and the third DNA sequence independently comprises an IRES element and/or a self-cleaving 2A peptide. In one embodiment, at least one E1a regulatory sequence Pea3 binding site, or a functional portion thereof of the adenoviral vector, is modified or deleted. In another embodiment, a sequence between two Pea3 sites of the adenoviral vector is deleted. In one embodiment, the adenoviral vector comprises a modified E3 region. In another embodiment the adenoviral vector comprises a nucleic acid sequence at least 95% identical in an E3 region to vector d1327. In another embodiment, the adenoviral vector comprises a nucleic acid sequence at least 85% identical in an E3 region to vector d1327. In another embodiment, the adenoviral vector comprises a nucleic acid sequence at least 75% identical in an E3 region to vector d1327.

[0016] In one embodiment, the chimeric human IL-12 polypeptide comprises a p40 polypeptide, a p35 polypeptide, and a linker polypeptide.

[0017] In another aspect is provided a method for treating a tumor in a human subject in need thereof, comprising administering to the human with the tumor a therapeutic amount of the pharmaceutical composition of the first aspect by systemic or intratumoral administration.

[0018] In another aspect is provided method for treating a tumor in a human subject in need thereof, comprising administering to the human with the tumor a therapeutic amount of the pharmaceutical composition of the second aspect by systemic or intratumoral administration.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 is a cartoon illustrating transcription factor binding regulation of conformational structure/activity of E1a enhancer region.

[0020] FIG. 2 is an illustration of a vector map demonstrating an adenoviral vector expressing two immunomodulatory polypeptides.

[0021] FIG. 3 is an illustration of a vector map demonstrating an adenoviral vector expressing at least one immunomodulatory polypeptide at an E4 site.

[0022] FIG. 4 is an illustration of the TRZ200 virus genome: an E1b 19k empty, E3-deleted virus.

[0023] FIG. 5 is an illustration of a vector map showing the plasmid comprising the TRZ6 hIL-12 plasmid.

[0024] FIG. 6A, FIG. 6B, FIG. 6C, FIG. 6D, FIG. 6E, FIG. 6F, FIG. 6G, FIG. 6H, FIG. 6I, FIG. 6J, FIG. 6K, and FIG. 6L are a series of graphs showing results of treatment of tumor bearing mice (n=8 in each group) with oncolytic viruses comprising various transgenes, with or without anti-PD-L1. FIG. 6A shows the activity of various oncolytic viruses compared to the empty virus ("d19k"), 38 days after cell implantation (primary tumor). Black bars represent virus alone and hatched bars represent virus+anti-PD-L1 antibody. FIG. 6B is a graph comparing the average tumor size (primary tumor) over time of tumors injected with virus buffer (black circles), empty vector (blue solid squares), anti-PD-L1 alone (antibody given on days 16, 20, 24, and 28, right-hand arrow in each pair of arrows), each of five viruses alone (CTLA-4, IL-12, IL-7, CD70, and IL-10) or combined with anti-PD-L1 antibody. FIG. 6C is a similar graph showing the remaining three viruses: OX40L, CD40L, and GM-CSF. Additional mouse treatments shown are as follows: FIG. 6D, virus buffer and control IgG only (left) and virus buffer and anti-PD-L1 antibody (right); FIG. 6E, d19k (empty virus) and control IgG only (left) and d19k and anti-PD-L1 antibody (right); FIG. 6F, CTLA-4 virus with control IgG (left) or anti-PD-L1 (right); FIG. 6G, IL-12 virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6H, GM-CSF virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6I, IL-7 virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6J, CD40L virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6K, L10 trap virus with control IgG (left) or anti-PD-L1 antibody (right); and FIG. 6L, OX40L virus with control IgG (left) or anti-PD-L1 antibody. The thick line in each graph shows the average tumor volume in mm.sup.3. The pairs of arrows on the x-axis represent day of treatment with virus (intratumoral, left arrows) and the anti-PD-L1 antibody, if used (intraperitoneal, right arrows).

[0025] FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, FIG. 7F, FIG. 7G, FIG. 7H, FIG. 7I, FIG. 7J, FIG. 7K, FIG. 7L, FIG. 7M, FIG. 7N, FIG. 7O, FIG. 7P, FIG. 7Q, FIG. 7R, FIG. 7S, FIG. 7T, FIG. 7U, FIG. 7V, FIG. 7W, FIG. 7X, FIG. 7Y, FIG. 7Z, and FIG. 7AA are a series of graphs showing treatment of tumor bearing mice (n=8 in each group) with single and combinations of oncolytic viruses comprising various transgenes, with or without anti-PD-L1 treatment. The left-hand panel of each Figure represents the primary tumor into which the virus was injected; the right-hand panel represents the contralateral tumor. The thick line in each graph shows the average tumor volume in mm.sup.3. The pairs of arrows on the x-axis represent day of treatment with virus (intratumoral, left arrows) and antibody (intraperitoneal, right arrows). A summary of the responses of the 8 mice is shown in a table at the bottom of each graph, wherein CR=Complete Response (tumor volume=0) and PR=Partial Response (tumor volume on last day of measurements is smaller than tumor volume on the first day of measurements). Treatments shown are as follows: FIG. 7A, virus buffer only; FIG. 7B, empty virus only (TRZ000); FIG. 7C, TRZ010 (IL-10trap)+empty virus; FIG. 7D, TRZ011 (OX40 ligand)+empty virus; FIG. 7E, TRZ009 (CD70)+empty virus; FIG. 7F, TRZ007 (IL-7)+empty virus, FIG. 7G, TRZ002 (IL-12)+empty virus; FIG. 7H, TRZ004 (GM-CSF)+empty virus; FIG. 7I, TRZ003 (flagellin)+empty virus; FIG. 7J, TRZ002+TRZ010; FIG. 7K, TRZ002+TRZ007; FIG. 7L, TRZ007+TRZ010; FIG. 7M, TRZ011+TRZ004; FIG. 7N, TRZ009+TRZ003; FIG. 7O, TRZ002+TRZ009; FIG. 7P, TRZ007+TRZ009; FIG. 7Q, TRZ007+TRZ004; FIG. 7R, TRZ002+TRZ011; FIG. 7S, TRZ010+TRZ004; FIG. 7T, TRZ002+TRZ004; FIG. 7U, virus buffer and anti-PD-L1; FIG. 7V, TRZ002+empty virus+anti-PD-L1; FIG. 7W, TRZ009+anti-PD-L1; FIG. 7X, TRZ007+empty virus+anti-PD-L1; FIG. 7Y, TRZ002+TRZ007+anti-PD-L1; FIG. 7Z, TRZ007+TRZ009+anti-PD-L1; and FIG. 7AA, TRZ002+TRZ009+anti-PD-L1, 7BB.

[0026] FIG. 8A and FIG. 8B are schematic representations of the rationale for modifications of the E1a Enhancer region of adenoviral vectors, in which Pea3 sites are altered, moved, or deleted in order to produce vectors with a variety of expression characteristics. FIG. 8A is an illustration of a wild-type adenoviral genome (top) and the TAV-255 adenoviral construct in which residues -305 to -255 are deleted (bottom). FIG. 8B is an illustration of the potential method of action of the TAV-255 construct, in which the deletion removes Pea3 sites II and III, which moves Pea3 sites IV and V closer to the promoter as distal control elements.

[0027] FIG. 9A, FIG. 9B, FIG. 9C, FIG. 9D, FIG. 9E, FIG. 9F, FIG. 9G, FIG. 9H, FIG. 9I, FIG. 9J, FIG. 9K, FIG. 9L, FIG. 9M, FIG. 9N, FIG. 9O, FIG. 9P, FIG. 9Q, FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, FIG. 9V, FIG. 9W, FIG. 9X, FIG. 9Y, and FIG. 9Z are a series of graphs showing treatment of tumor bearing mice (n=8 in each group) with dual transgene (either expressed from both E1 and E3, or dual transgenes expressed from either E1 or E3) oncolytic viruses comprising various transgenes, with either anti-PD-L1 antibody or anti-PD-1 antibody treatment. FIG. 9A is a cartoon of the contrast between the single transgene constructs (top) used in the virus mixing examples, and the dual transgene vectors used to make the E1/E3 transgene adenoviruses. FIG. 9B shows the results of mice injected i.t. with Empty virus +/-anti-PD-L1 or with TRZ-409 (IL-12/IL-7 dual transgene) +/-anti-PD-L1. The tumor volume of the injected tumor is shown in the left panel, and the tumor volume of the contralateral tumor is shown in the right panel. For each pair of arrows, the left arrow indicates virus injection and the right arrow indicates anti-PD-L1 injection. As can be seen for both the primary and contralateral tumors, TRZ-409 injection reduced tumor volume significantly compared to empty virus. The combination with anti-PD-L1 was slightly more efficacious in this study. FIG. 9C shows the results of a second experiment using the inverse of TRZ-409, TRZ-403, in which the IL-7 transgene occupies the E1 region and the IL-12 gene occupies the E3 region (which has a stronger promoter than the E1). As can be seen in the Figure, TRZ-403 strongly inhibits primary and distant tumor growth, with or without anti-PD-L1. Plasma levels of IL-12 and IFN-.gamma. (FIG. 9D) for all mice injected with TRZ-403 show that expression of the transgenes is well tolerated. The study was extended for all mice having tumors over 500 mm.sup.3. As can be seen in the FIG. 9E, mice injected with TRZ-403 had a much higher percentage of survival over TRZ-409 at the time end of the study (70 days). Mice having primary tumors injected with TRZ-403 (IL-7+IL-12), TRZ-403+anti-PD-L1, TRZ-403+control IgG, or TRZ-409 (IL-12+IL-7), and controls including untreated mice and mice injected with empty vector TRZ-d19K with anti-PD-L1, anti-PD-1, or a control IgG. As can be seen in the Figure, mice injected with TRZ-403 had a much higher percentage of survival over TRZ-409 at the time end of the study (70 days). Both TRZ-403 and TRZ-409 showed efficacy over the controls; all mice receiving control injections were deceased by day 56 of the study. FIG. 9F compares a mixture of two single transgene viruses with a dual transgene virus having the same transgenes. As can be seen in the primary tumor (left panel) TRZ-403 showed the most efficacy in reducing tumor volume, followed by the mixture of IL-7 and IL-12 single transgene viruses. The single transgene IL-12 virus showed a small amount of efficacy by comparison. In the contralateral tumor, however (right panel) only the dual transgene virus, TRZ-403, reduced the tumor volume, showing significant superiority over the mixture of viruses. FIG. 9G, FIG. 9H, FIG. 9I, FIG. 9J, FIG. 9K, FIG. 9L, FIG. 9M, FIG. 9N, FIG. 9O, FIG. 9P, FIG. 9Q, FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, FIG. 9V, FIG. 9W, FIG. 9X, FIG. 9Y, and FIG. 9Z show comparisons of anti-tumor activity of various dual transgene viruses and controls, including comparison with antibody treatments. FIG. 9G, FIG. 9H, FIG. 9I, FIG. 9J, FIG. 9K, FIG. 9L, FIG. 9M, FIG. 9N, FIG. 9O, FIG. 9P, FIG. 9Q, FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, FIG. 9V, FIG. 9W, FIG. 9X, FIG. 9Y, and FIG. 9Z show the primary tumor in the left panel and the contralateral tumor in the right panel. All viruses were administered intratumorally and the antibodies were administered intraperitoneally. Viral dose regimens vary and are tabulated in Table 7 (Example 12); all antibodies are administered at a dose of 2504. FIG. 9G shows the tumor activity in untreated animal controls; FIG. 9H shows TRZ000 (E1-Empty/E3 Intact); FIG. 9I, FIG. 9J, and FIG. 9K show TRZ002 (E1-mIL-12/E3 Del); FIG. 9L, FIG. 9M, and FIG. 9N show TRZ510 (E1-mIL-7-P2A-mIL-12/E3 Del); FIG. 9O, FIG. 9P, and FIG. 9Q show TRZ021 (E1-empty/E3-mIL-2); FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, and FIG. 9V show TRZ421 (E1-mIL-12/E3-mIL-2); FIG. 9W shows the combination of TRZ002 (E1-mIL-12/E3 Del)+Anti-CTLA4 antibody (see Table 7 for doses); FIG. 9X shows anti-PD-1 antibody treatment alone, FIG. 9Y shows anti-CTLA4 antibody alone, and FIG. 9Z shows results of treatment with the combination of anti-CTLA-4 and anti-PD-1 antibodies (both from BioXCell).

[0028] FIG. 10A FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F, and FIG. 10G are a series of graphs showing measurement of in vitro expression of transgenes cloned into the E1 or E3 site of oncolytic adenoviruses. A549 or ADS12 cells were infected with TRZ000 (empty virus), TRZ403 (E1 IL-7/E3 IL-12), TRZ416 (E1 OX40L/E3 IL-12), TRZ421 (E1 IL-12/E3 IL-2), TRZ510 (E1 IL-7-P2A-IL-12/E3), or TRZ512 (E1-IL-12-P2A-IL-7/E3) at a multiplicity of infection (MOI) of 10 or 25. Forty-eight hours after infection, the supernatants were harvested, clarified by centrifugation, and assayed for protein expression by standard ELISA methods (mouse IL-12, mouse IL-2, and mouse IL-7) using Quantikine.RTM. kits, (R&D Systems); and mouse OX40L using a DuoSet.RTM. kit, (R&D Systems). Expression of transgenes from the adenovirus E1 site is shown for IL-7 (TRZ403, FIG. 10A, A549 cells), IL-7 (TRZ510 and TRZ512, FIG. 10B, ADS-12 cells), OX40L (TRZ416, FIG. 10C, A549 cells), IL-12 (TRZ421), FIG. 10D, A549 cells), IL-12 (TRZ510 and TRZ512, FIG. 10E, ADS-12 cells). Expression of transgenes from the E3 site is shown for IL-12 (TRZ403 and TRZ416, FIG. 10F, A549 cells) and IL-2 (TRZ421, FIG. 10G, A549 cells). As can be seen in the Figures, all transgenes were expressed well from either the E1 or E3 site.

[0029] FIG. 11A FIG. 11B, FIG. 11C, FIG. 11D, and FIG. 11E are a series of graphs showing measurement of in vitro function of transgenes cloned into the E1 or E3 site of oncolytic adenoviruses. A549 cells were infected with TRZ510 (E1 IL-7-P2A-IL-12/E3), TRZ512 (E1 IL-12-P2A-IL-7/E3), TRZ403 (E1 IL-7/E3 IL-12), and TRZ416 (E1 OX40L/E3 IL-12) at a multiplicity of infection (MOI) of 10 or 25. Forty-eight hours after infection, the supernatants were harvested, clarified by centrifugation, and assayed for biological function of secreted IL-12 using HEK-Blue.TM. IL-12 cells or of secreted IL-2 using CTLL-2 cells. Function of IL-12 transgenes in HEK-Blue IL-12 cells is shown for IL-12 in supernatants expressed from the E1 region (FIG. 11A, TRZ510; FIG. 11B, TRZ512) and from the E3 region (FIG. 11C, TRZ403; FIG. 11D, TRZ416). Function of IL-2 transgenes in CTLL-2 cells is shown for supernatants expressed from the E3 region is shown in FIG. 11E (TRZ421). As can be seen in the Figures, all transgenes were functional when expressed from the E1 or E3 sites, including those connected with a P2A sequence.

DEFINITIONS

[0030] The term "replicating virus" is meant to include a virus that undergoes the process of intracellular viral multiplication, consisting of the synthesis of proteins, nucleic acids, and sometimes lipids, and their assembly into a new infectious particle.

[0031] As used herein, the term "adenovirus" refers to any of a group of DNA-containing viruses (small infectious agents) that cause conjunctivitis and upper respiratory tract infections in humans. Adenoviral vectors are described in Peng, Z., "Current Status of Gendicine in China: Recombinant Human Ad-p53 Agent for Treatment of Cancers," Hum Gene Ther 16:1016-1027 (2005); No authors listed, "The End of the Beginning: Oncolytic Virotherapy Achieves Clinical Proof-of-concept," Mol Ther 13:237-238 (2006); Vile et al., "The Oncolytic Virotherapy Treatment Platform for Cancer: Unique Biological and Biosafety Points to Consider," Cancer Gene Ther 9:1062-1067 (2002); Harrison et al., "Wild-type Adenovirus Decreases Tumor Xenograft Growth, but Despite Viral Persistence Complete Tumor Responses are Rarely Achieved--Deletion of the Viral E1b-19-kD Gene Increases the Viral Oncolytic Effect," Hum Gene Ther 12:1323-1332 (2001); Kim et al., "Clinical Research Results with d11520 (Onyx-015), a Replication-selective Adenovirus for the Treatment of Cancer: What Have We Learned?," Gene Ther 8:89-98 (2001); and Thorne et al., "Oncolytic Virotherapy: Approaches to Tumor Targeting and Enhancing Antitumor Effects," Semin Oncol 32:537-548 (2005), each of which is hereby incorporated by reference in their entirety. Adenoviral positions referenced herein are to positions in Adenovirus type 5 (GenBank 10 accession #M73260; the virus is available from the American Type Culture Collection, Rockville, Md., U.S.A., under accession number VR-5). It will be understood that corresponding positions can be identified in other adenovirus vectors by alignment using BLAST 2.0 under default settings (Altschul et al., J. Mol. Biol. 215:403-410 (1990)). Software for performing BLAST analyses is publicly available on the Web through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov/).

[0032] Current research in the field of viral vectors is producing improved viral vectors with high-titer and high-efficiency of transduction in mammalian cells (see, e.g., U.S. Pat. No. 6,218,187 to Finer et al., which is hereby incorporated by reference in its entirety). Such vectors are suitable in the present invention, as is any viral vector that comprises a combination of desirable elements derived from one or more of the viral vectors described herein. It is not intended that the expression vector be limited to a particular viral vector.

[0033] Certain "control elements" or "regulatory sequences" can also be incorporated into the vector-construct. The term "control elements" refers collectively to promoter regions, polyadenylation signals, transcription termination sequences, upstream regulatory domains, origins of replication, internal ribosome entry sites ("IRES"), enhancers, and the like, which collectively provide for the replication, transcription, and translation of a coding sequence(s) in a recipient cell. Not all of these control elements need always be present so long as the selected coding sequence is capable of being replicated, transcribed, and translated in an appropriate host cell.

[0034] The term "promoter region" is used herein in its ordinary sense to refer to a nucleotide region comprising a DNA regulatory sequence, wherein the regulatory sequence is derived from a gene which is capable of binding RNA polymerase and initiating transcription of a downstream (3'-direction) coding sequence. Transcriptional control signals in eukaryotes comprise "promoter" and "enhancer" elements. Promoter and enhancer elements have been isolated from a variety of eukaryotic sources, including genes in yeast, insect, and mammalian cells, and viruses. Analogous control elements, i.e., promoters, are also found in prokaryotes. Such elements may vary in their strength and specificity. For example, promoters may be "constitutive" or "inducible."

[0035] A constitutive promoter is a promoter that directs expression of a gene throughout the development and life of an organism. Examples of some constitutive promoters that are widely used for inducing expression of transgenes include the cytomegalovirus (CMV) early promoter, those derived from any of the several actin genes, which are known to be expressed in most cells types (U.S. Pat. No. 6,002,068 to Privalle et al., which is hereby incorporated by reference in its entirety), and the ubiquitin promoter, which is a gene product known to accumulate in many cell types.

[0036] To ensure efficient expression, 3' polyadenylation regions can be present to provide for proper maturation of the mRNA transcripts. The 3' polyadenylation region will preferably be from the adenovirus sequence downstream of the inserted transgene, but the native 3'-untranslated region of the immunomodulatory gene may be used, or an alternative polyadenylation signal from, for example, SV40, particularly including a splice site, which provides for more efficient expression, could also be used. Alternatively, the 3'-untranslated region derived from a gene highly expressed in a particular cell type could be fused with the immunomodulatory gene.

[0037] "Inhibitors," "activators," and "modulators" of expression or of activity are used to refer to inhibitory, activating, or modulating molecules, respectively, identified using in vitro and in vivo assays for expression or activity of a described target protein, e.g., ligands, agonists, antagonists, and their homologs and mimetics. The term "modulator" includes inhibitors and activators. Inhibitors are agents that, e.g., inhibit expression or bind to, partially or totally block stimulation or protease inhibitor activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of the described target protein, e.g., antagonists. Activators are agents that, e.g., induce or activate the expression of a described target protein or bind to, stimulate, increase, open, activate, facilitate, enhance activation or protease inhibitor activity, sensitize or up regulate the activity of described target protein (or encoding polynucleotide), e.g., agonists. Modulators include naturally occurring and synthetic ligands, antagonists and agonists (e.g., small chemical molecules, antibodies and the like that function as either agonists or antagonists). Such assays for inhibitors and activators include, e.g., applying putative modulator compounds to cells expressing the described target protein and then determining the functional effects on the described target protein activity, as described above. Samples or assays comprising described target protein that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition of a described target protein is achieved when the activity value relative to the control is about 80%, optionally 50% or 25, 10%, 5% or 1%. Activation of the described target protein is achieved when the activity value relative to the control is 110%, optionally 150%, optionally 200, 300%, 400%, 500%, or 1000-3000% or higher.

[0038] "Antibody" refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.

[0039] Naturally occurring immunoglobulins have a common core structure in which two identical light chains (about 24 kD) and two identical heavy chains (about 55 or 70 kD) form a tetramer. The amino-terminal portion of each chain is known as the variable (V) region and can be distinguished from the more conserved constant (C) regions of the remainder of each chain. Within the variable region of the light chain is a C-terminal portion known as the J region. Within the variable region of the heavy chain, there is a D region in addition to the J region. Most of the amino acid sequence variation in immunoglobulins is confined to three separate locations in the V regions known as hypervariable regions or complementarity determining regions (CDRs) which are directly involved in antigen binding. Proceeding from the amino-terminus, these regions are designated CDR1, CDR2 and CDR3, respectively. The CDRs are held in place by more conserved framework regions (FRs). Proceeding from the amino-terminus, these regions are designated FR1, FR2, FR3, and FR4, respectively. The locations of CDR and FR regions and a numbering system have been defined by, e.g., Kabat et al. (Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, U.S. Government Printing Office (1991)).

[0040] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (V.sub.L) and variable heavy chain (V.sub.H) refer to these light and heavy chains respectively.

[0041] Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'.sub.2, a dimer of Fab which itself is a light chain joined to V.sub.H-C.sub.H1 by a disulfide bond. The F(ab)'.sub.2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'.sub.2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see FUNDAMENTAL IMMUNOLOGY (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).

[0042] For preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). "Monoclonal" antibodies refer to antibodies derived from a single clone. Techniques for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies. Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).

[0043] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity.

[0044] A "humanized" antibody is an antibody that retains the reactivity of a non-human antibody while being less immunogenic in humans. This can be achieved, for instance, by retaining the non-human CDR regions and replacing the remaining parts of the antibody with their human counterparts. See, e.g., Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984); Morrison and Oi, Adv. Immunol., 44:65-92 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988); Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3):169-217 (1994).

[0045] As used herein, the terms "treat" and "treating" in the context of the administration of a therapy refers to a treatment/therapy from which a subject receives a beneficial effect, such as the reduction, decrease, attenuation, diminishment, stabilization, remission, suppression, inhibition or arrest of the development or progression of cancer, or a symptom thereof. In certain embodiments, the treatment/therapy that a subject receives results in at least one or more of the following effects: (i) the reduction or amelioration of the severity of cancer and/or a symptom associated therewith; (ii) the reduction in the duration of a symptom associated with cancer; (iii) the prevention in the recurrence of a symptom associated with cancer; (iv) the regression of cancer and/or a symptom associated therewith; (v) the reduction in hospitalization of a subject; (vi) the reduction in hospitalization length; (vii) the increase in the survival of a subject; (viii) the inhibition of the progression of cancer and/or a symptom associated therewith; (ix) the enhancement or improvement the therapeutic effect of another therapy; (x) a reduction or elimination in the cancer cell population; (xi) a reduction in the growth of a tumor or neoplasm; (xii) a decrease in tumor size; (xiii) a reduction in the formation of a tumor; (xiv) eradication, removal, or control of primary, regional and/or metastatic cancer; (xv) a decrease in the number or size of metastases; (xvi) a reduction in mortality; (xvii) an increase in cancer-free survival rate of patients; (xviii) an increase in relapse-free survival; (xix) an increase in the number of patients in remission; (xx) a decrease in hospitalization rate; (xxi) the size of the tumor is maintained and does not increase in size or increases the size of the tumor by less 5% or 10% after administration of a therapy as measured by conventional methods available to one of skill in the art, such as MRI, X-ray, and CAT Scan; (xxii) the prevention of the development or onset of cancer and/or a symptom associated therewith; (xxiii) an increase in the length of remission in patients; (xxiv) the reduction in the number of symptoms associated with cancer; (xxv) an increase in symptom-free survival of cancer patients; and/or (xxvi) limitation of or reduction in metastasis. In some embodiments, the treatment/therapy that a subject receives does not cure cancer, but prevents the progression or worsening of the disease. In certain embodiments, the treatment/therapy that a subject receives does not prevent the onset/development of cancer, but may prevent the onset of cancer symptoms.

[0046] As used herein, the term "in combination" in the context of the administration of (a) therapy(ies) to a subject, refers to the use of more than one therapy. The use of the term "in combination" does not restrict the order in which therapies are administered to a subject. A first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy to a subject.

[0047] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity over a specified region, e.g., of the entire polypeptide sequences or specific region, if indicated), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be "substantially identical."

[0048] For sequence comparison, one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[0049] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full-length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison are conducted by a BLAST 2.0 algorithm, which is described in Altschul et al. (1990) J. Mol. Biol. 215:403-410. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0050] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

DETAILED DESCRIPTION

[0051] Disclosed herein are compositions and methods of treating cancer in a subject. Provided are replicating viral vectors, specifically oncolytic adenoviral vectors, that contain one or more recombinant nucleic acid sequences encoding therapeutic polypeptides.

[0052] Oncolytic adenovirus (AV) expressing a transgene display highly oncolytic and immunogenic properties. Therefore, the recombinant adenoviral vectors provided herein have the potential to have broad activity against a primary tumor infected with adenovirus but also against tumors in the metastatic disease setting. In some embodiments, the metastatic tumors need not be directly injected with virus nor does the virus injected into the primary site travel to the metastatic setting (e.g. through the blood stream).

[0053] However, due to expression of an immune stimulatory transgene from the adenovirus (for example, including but not limited to an E1b 19K deleted region in an exemplary vector such as TAV-255 (e.g., TAV-255 .DELTA.19)), the immune system will be primed to fight cancer systemically in the entire body of the cancer patient as long as the metastatic tumor cells express the same tumor antigens as the primary tumor cells. Since metastases are derived from the primary tumors and genetically very similar to the primary tumor cells, metastatic tumor growth will be inhibited, in some embodiments, to the same extent as the primary tumor.

[0054] Provided are adenoviruses as described herein. In another aspect, a cell transformed with any one of the recombinant adenoviruses described herein is provided.

[0055] In another aspect, a method is provided of selectively expressing a peptide in a target cell comprises contacting the target cell with any one of the recombinant adenoviruses described herein. In one aspect, the recombinant adenovirus comprises a E1a regulatory sequence deletion mutant operably linked to a nucleotide sequence encoding a peptide, e.g., a peptide associated with viral replication or with cancer.

[0056] Also provided herein are methods of adenoviral therapy that utilize the oncolytic adenoviruses of the instant invention as adenoviral vectors that express one, two, or more recombinant immunomodulatory genes. The oncolytic adenovirus contains a heterologous gene that encodes a therapeutic protein, incorporated within the viral genome, such that the heterologous gene is expressed within an infected cell. A therapeutic protein, as used herein, refers to a protein that provides one or more therapeutic benefit when expressed in a given cell. In particular, the therapeutic benefit includes recruitment of the host immune system to the tumor.

Modified Regulatory Regions

[0057] E1a is the first protein produced by an adenovirus upon infection of a cell, activating other adenoviral promoters and facilitating infected cells to enter cell division. Rendering expression of this protein under tumor-selective control is an effective means of limiting expression of viral proteins and oncolysis to tumor cells.

[0058] Normal cells require mitogenic growth signals (GS) before they can move from a quiescent state into an active proliferative state. Tumor cells are able to generate many of their own growth signals or mimic normal growth signals, and transcription factors such as E2F1 and Pea3 are commonly overexpressed in tumor cells at levels that can cooperate in forming conformational structures optimal for driving E1a transcription during adenovirus infection and replication. (Hanahan D, Weinberg R A. The Hallmarks of Cancer. Cell 2000; 100: 57-70; de Launoit Y, Chotteau-Lelievre A, Beaudoin C, Coutte L, Netzer S, Brenner C et al., The PEA3 Group of ETS-Related Transcription Factors: Role in Breast Cancer Metastasis, Adv Exp Med Biol 2000; 480: 107-116; Bruder J T, Hearing P: Cooperative Binding of EF-1A to the E1A Enhancer Region Mediates Synergistic Effects on E1A Transcription During Adenovirus Infection. J Virol 1991; 65:5084-5087).

[0059] Small deletions selectively targeting the binding sites for E2F1 and Pea3 sites in the E1a enhancer region are an alternative and less disruptive method than complete replacement of the E1a enhancer region with a transcriptionally restricted promoter element. Cooperative binding and transcriptionally optimized conformation of the E1a enhancer region could still take place due to the over-abundance of transcription factors found in tumor cells, while in normal, non-dividing cells, the disruption of binding sites would further inhibit the ability to form optimized conformations in the limiting level of mitogenic growth signals.

[0060] Thus, disclosed herein are methods of engineering adenoviral vectors via the Pea3 binding sites. The five Pea3 transcription factor binding sites, also known as E1AF (or originally as EF-1A-enhancer binding factor to the E1a core motif) have differential effects on the production of E1a mRNA levels as demonstrated by specific deletions of individual and paired sites. The murine Pea3 sites are described herein as Pea3 sites I, II, III, IV, and V. The main binding sites for Pea3 are sites I and III, while sites II, IV, and V are slightly degenerate versions. Pea3 binds cooperatively between sites II and III, IV and V, and II and I, and this cooperative binding activates E1a transcription. (see, e.g., Hearing (J. Virol 65, 1991, Mol Cell Biol 9, 1989, and Nuc Acids Res 20, 1992). Pea3 itself is a dimer of both a and .beta. subunits, where the .alpha. subunit makes the primary DNA contact and the .beta. subunit forms a heteromultimeric complex with the .beta. subunit both in solution or on a dimeric binding site. During normal infection conditions, binding at sites I and III, followed by the cooperative binding at site II would cause conformational changes that serve to bring this protein/DNA complex closer to the activation transcription factor (ATF) binding site and TATA box for full activation of E1a mRNA expression. The two lower affinity sites, Pea3 IV and Pea3 5, do not appear to contribute much to activation under these normal circumstances, as they may be too far away or unoccupied. Deletion of site II causes the greatest reduction in transcriptional activity, pointing to the importance of the cooperative binding effect it has for sites III and I in activating transcription, presumably through a conformational change. Deletion of either site III or I had much less of a reduction, since presumably you could still have cooperative binding between site II and the remaining site III or I. Deletion of both sites I and III (but not II) reduces transcription to the levels seen with Pea3 site II deletion alone, and the combination of deleting both sites III and II, or sites II and I also results in similar (but not greater) levels of reduction.

[0061] Deletion of the region encompassing sites III and II removes this cooperative binding capacity derived from site II, but it also moves sites IV and V closer to site I. Although lower affinity, sites IV and V do show cooperative binding, and by moving them closer to site I, binding at these three sites may be able to mimic the conformation change normally occurring with binding of sites I-III, leading to transcriptional activation. Because sites IV and V are lower affinity sites, there may not be enough of this transcription factor around in normal cells to get full binding on the deleted construct for activation, but there are several publications reporting increased levels of E1AF/Pea3 with tumor progression and invasiveness (i.e., Horiuchi S. et. al., J Pathol 2003 August; 200(5): 568-76), indicating that tumor cells may have enough E1AF to bind the lower affinity binding sites IV and V, along with site I, and potentially lead to a conformational change needed to activate transcription of E1a in tumor but not normal cells with this deleted virus.

[0062] The present invention provides replicating adenoviruses. In some embodiments, the replicating vectors of the instant invention contain recombinant (e.g., exogenous) transgene(s) expressing immunomodulatory polypeptides that are controlled by endogenous adenovirus early promoters, thereby driving meaningfully higher expression levels than can be generally achieved in replication deficient viruses. In addition to the enhanced anti-tumor efficacy resulting from tumor-specific oncolysis from the replicating adenovirus, the higher expression levels from the recombinant transgenes in a replicating virus results in enhanced immunomodulatory effect(s) over the lower expression levels in replication deficient viruses.

[0063] In one aspect, a recombinant virus comprises a modified E1a regulatory sequence, wherein at least one Pea3 binding site, or a functional portion thereof, is deleted. In one aspect, a sufficient number of nucleotides in the range of -305 to -141 are retained to maintain functional activity of the Ad packaging signal function and (near) optimal transcription of the E1a protein in tumor but not growth arrested normal cells.

[0064] Additional deletions or modifications of individual or combinations of Pea3V, Pea3IV, Pea3III, Pea3II and/or E2F1 binding sites between base pairs -394 and -218 designed to inhibit binding of Pea3 and/or E2F1 to these sites and take part in cooperative binding induced conformational changes in the E1a enhancer region are also encompassed by this description.

[0065] In one aspect, at least one of Pea3 II, Pea3 III, Pea3 IV, and Pea3 V, or a functional portion thereof, is deleted or modified (e.g., at least one nucleotide of the sequence is changed or an additional nucleotide is inserted into the sequence). In another aspect, at least one of Pea3 II and Pea3 III, or a functional portion thereof, is deleted or modified. In one aspect, Pea3 II or a functional portion thereof, and Pea3 III or a functional portion thereof, is deleted or modified. In another aspect, at least one of Pea3 IV and Pea3 V, or a functional portion thereof, is deleted or modified. In another aspect, Pea3 I, or a functional portion thereof, is retained. By "retained" is meant that the element is present in the recombinant adenoviral vector, preferably at the same location as a reference adenoviral vector. In one aspect, at least one E2F1 binding site, or a functional portion thereof, is retained.

[0066] In one aspect, the vector is d1309-6, TAV-255, d155, d1200, d1230, or d1200+230. In another aspect, the vector is TAV-255. In another aspect, the E1a deletions in d1309-6, TAV-255, d155, d1200, d1230, d1200+230, or other E1a modifications affecting Pea3 and/or E2F1 binding sites between -394 to -218, are paired with a non-d1309 based E3 deletion such as the E3 deletion found in pBHG10 (Microbix, Ad5 base pairs (bp) 28133-30818), d1327 (Ad5 bp 28593-30470) or a similar size E3 deletion such that >3 kb of exogenous DNA can be successfully packaged and expressed from a recombinant adenovirus with the E1a deletions listed above, in combination with a deletion between the start site of the E1b 19K protein and the start site of the E1b 55K protein of approximately 202 base pairs. In one aspect, the vector is a d1309 vector having one or more mutations in reference to the wild type sequence of Ad5 (see, e.g., Chroboczek et al., Virology (1992) January; 186(1):280-5, herein incorporated by reference), including a disruption in the coding sequences for one or more of the 10.4K, 14.5K, and 14.7K proteins in the E3 region.

[0067] In one aspect, a recombinant virus selectively expresses at least one E1a isoform, e.g., Ela-12S or Ela-13S. In one aspect, the sequence encoding the E1a isoform is operably linked to a modified E1a regulatory sequence, wherein at least one Pea3 binding site, or a functional portion thereof, is deleted or modified.

[0068] In one aspect, a recombinant virus comprises a DNA sequence, e.g., a transgene, inserted into an E1b-19K insertion site. In one aspect, the insertion site is located between the start site of E1b-19K and the start site of E1b 55K. In another aspect, the insertion site comprises a deletion of 202 base pairs following the start site of E1b-19K. A transgene (also, "insert") may be a full natural sequence of the gene of interest or a fragment thereof. It may be modified too include a Kozak sequence, stop codon, or other regulatory elements. A transgene may include one or more endonuclease restriction sites.

[0069] In another aspect, expression the transgene is operably linked to a modified E1a regulatory sequence, wherein at least one Pea3 binding site, or a functional portion thereof, is modified or deleted. The transgene may be located in the E1, E2, E3 and/or E4 regions of the adenovirus but its expression is controlled by E1a mediated activation of the endogenous upstream adenovirus promoter, generating high levels of transgene expression only during E1a mediated viral replication.

[0070] In specific embodiments, the transgene is located in the E3 region. Exogenous transgenes can be inserted into one or more deleted regions of the adenovirus E3 region, generally such transgenes are inserted into the adenoviral vector as to have their expression controlled by the endogenous E3 promoter (Luo J et al, Clin Cancer Res 2008: 14 2450-2457). This results in high levels of transgene expression that are specifically expressed during periods of viral replication, as the E3 promoter only becomes transcriptionally active during these times. Using a modified adenovirus backbone, such as the E1a enhancer modification described herein, to limit viral replication to infected tumor cells, expression from the introduced transgene is also limited to infected tumor cells and, generally, not normal cells. In certain embodiments, the entire E3 region, or a substantial portion of the E3 region, is deleted.

[0071] In specific embodiments, the transgene is located in the E4 region. In a similar fashion to inserting exogenous transgenes into deleted regions in the E3 or E1 regions of adenovirus, there are regions in the E4 region of adenovirus that can be deleted without significant effect on viral growth characteristics (Gao, G P et al, J. Virol 1996: 70; 8934-8943). Generally, at least ORF3 and/or ORF6 are retained in the adenoviral vector in which the remainder of the E4 region. It should be possible to insert a foreign transgene into one of these deletions in the E4 region and drive expression of this gene with the endogenous E4 promoter of adenovirus, restricting high level expression of this gene to conditions where viral replication is expected to occur.

Tumor-Directed Recombinant Immunomodulatory Polypeptide Production.

[0072] The adenoviruses described herein can be engineered to express an immunomodulatory agent or immunomodulatory polypeptide, e.g., a polypeptide agonist of a co-stimulatory signal of an immune cell. In some embodiments, the polypeptide agonist is an agonist of a T effector cell and/or the polypeptide agonist functions as a polypeptide antagonist of an inhibitory signal of an immune cell such as a regulatory T cell. As provided herein, an "immunomodulatory protein" or an "immunomodulatory polypeptide" includes any polypeptide or set of polypeptides capable of modulating (e.g., stimulating) the anti-tumor immune response induced by the adenovirus. Generally, an "immunomodulatory polypeptide" includes a desired immunostimulatory activity. An immunomodulatory polypeptide can include a set of polypeptides, linked or unlinked, that can form a multimer (e.g., a dimer) capable of modulating the anti-tumor immune response induced by adenovirus, e.g., IL-12 dimer formed from p40 and p35, with or without a linker. Immunomodulatory polypeptides can be full length proteins as occur in nature or can be fusions, variants, or fragments thereof that retain at least about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the immunomodulatory activity of the full-length protein.

[0073] As used herein, the term "agonist(s)" refers to a molecule(s) that binds to another molecule and induces an increased biological reaction. In a specific embodiment, an agonist is a molecule that binds to a receptor on a cell and triggers or stimulates one or more signal transduction pathways. For example, an agonist can include an antibody or ligand that binds to a receptor on a cell and induces one or more signal transduction pathways. In other embodiments, the agonist facilitates the interaction of the native ligand with the native receptor. As used herein, the term "antagonist(s)" refers to a molecule(s) that inhibits the action of another molecule, optionally without provoking an independent biological response itself. In a specific embodiment, an antagonist is a molecule that binds to a receptor on a cell and blocks or dampens the biological activity of an agonist. For example, an antagonist can include an antibody or ligand that binds to a receptor on a cell and blocks or dampens binding of the native ligand to the cell, optionally without inducing one or more signal transduction pathways. Another example of an antagonist includes an antibody or soluble receptor that competes with the native receptor on cells for binding to the native ligand, and thus, blocks or dampens one or more signal transduction pathways induced when the native receptor binds to the native ligand. A further example of an antagonist includes an antibody or soluble receptor that competes with the native receptor on cells for binding to the native ligand or blocks receptor internalization, and thus, blocks or dampens one or more signal transduction pathways induced when the native receptor binds to the native ligand.

[0074] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is a costimulatory ligand, e.g., GITR ligand (GITRL), OX40 ligand (OX40L), or CD40 ligand (CD40L). Expression of one or more costimulatory ligands in the tumor microenvironment and the specific binding to the cognate receptor results in an increase in activity of a tumor-infiltrating lymphocyte (TIL), such activity including TIL proliferation and cytokine release, thereby increasing the anti-tumor activity of the pharmaceutical composition.

[0075] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is a pro-inflammatory cytokine, e.g., GMCSF, IL-7, IL-12, or an IL-15 hybrid (e.g., a hybrid of IL-15 and IL-15 receptor alpha). Expression of one or more pro-inflammatory cytokine in the tumor microenvironment results in a tumor-localized increase in the inflammatory milieu, thereby increasing the anti-tumor activity of the pharmaceutical composition, and also increasing safety of the composition by decreasing or eliminating undesired effects of systemic administration of a pro-inflammatory cytokine.

[0076] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is an inhibitor (e.g., a "receptor trap" or a "trap") of an inhibitory cytokine, e.g., IL-10 or IL-27. In other embodiments, the immunomodulatory agent/inhibitor of an inhibitory cytokine is an antibody against, e.g., TGFB or IL-10R. Such inhibitory cytokines decrease T effector cell function. Expression of one or more inhibitory cytokine receptor traps in the tumor microenvironment results in a tumor-localized binding to and neutralization of the inhibitory cytokine, thereby reducing or preventing its inhibitory activity and increasing the anti-tumor activity of the pharmaceutical composition, and also increasing safety of the composition by decreasing or eliminating undesired effects of systemic administration of a blockage of an inhibitory cytokine.

[0077] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is an initiator of a localized immune response, e.g., a protein (e.g., secreted flagellin) that activates a toll-like receptor ligand such as TLR-5. Expression of one or more immune response initiators in the tumor microenvironment results in a tumor-localized immune response (e.g., infiltration of TILs and antigen presenting cells (APCs) and increasing the anti-tumor activity of the pharmaceutical composition.

[0078] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is an inhibitor (e.g., an antibody antagonist) of a co-inhibitory checkpoint molecule, e.g., CTLA4. Such inhibitory checkpoint molecules decrease T effector cell function. Expression of one or more inhibitory checkpoint molecules at the surface of an activated T cell (e.g., an activated T effector cell) attenuates the functional activity of the T cell. Thus, expression of an antagonist of the co-inhibitory checkpoint molecule in the tumor microenvironment results in blocking the co-inhibitory activity and increasing the anti-tumor activity of the pharmaceutical composition, and also increasing safety of the composition by decreasing or eliminating undesired effects of systemic administration of a blockage of a co-inhibitory checkpoint molecule.

[0079] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is a cluster of differentiation (CD) molecule or a ligand of a cluster of differentiation (CD) molecule such as CD27, e.g., CD70. Expression of a CD27 ligand in the tumor microenvironment results in a tumor-localized NK-mediated tumor clearance and promotes the adaptive immune response against the tumor, thereby increasing the anti-tumor activity of the pharmaceutical composition. Other suitable CD molecules include CD1d, CD2, CD3, CD4, CD5, CD6, CD7, CD8a, CD8b, CD9, CD21, CD25, CD37, CD40, CD49b, CD53, CD57, CD69, CD80, CD81, CD82, CD86, CD99, CD103, CD134, CD152, CD154, CD165, CD244, CD267, CD272, CD273, CD274, CD278, CD305, CD314, CD357, and CD360, or the ligands thereof, or any modulator (e.g., a stimulator or an inhibitor) thereof.

[0080] In specific embodiments, the immunomodulatory polypeptide expressed by the adenovirus is selected from a polypeptide provided in Table 1.

TABLE-US-00001 TABLE 1 Exemplary Immunomodulatory polypeptides SEQ ID Accession NO: Immunomodulatory Polypeptide Number(s) 1 GITR-Ligand (GITR-L; TNFSF18) NP_005083 2 GITR-Ligand (GITR-L; TNFSF18) NM_183391 3 CD28 ligand or agonist (CD80) EAW79565 4 TNF.alpha. CAA78745 5 Non-cleavable TNF.alpha. NM_013693 6 GM-CSF NM_009969 7 ICOS ligand or agonist NP_056074 8 4-1BB ligand or agonist AAA53134 (human) 9 OX40 ligand or agonist CAE11757 10 OX40 ligand NM_009452 11 CD40 ligand or agonist NP_000065 12 CD40 ligand NM_011616 13 CD27 ligand or agonist AAA36175 14 CD70 ligand or agonist NM_011617 15 Interleukin-2 (IL-2) AAB46883 16 Interleukin-7 (IL-7) AAH47698 17 Interleukin-7 (IL-7) NM_00837 18 Interleukin-12 (IL-12) alpha subunit AAD16432 19 Interleukin-12 (IL-12) beta subunit NP_005526 20 Interleukin-12 fusion polypeptide N/A 21 IL-15 CAA62616 22 IL-15 hybrid N/A 23 IL-10R TRAP (IL-10 antagonist) [alpha] NP_001549 24 IL-10R Trap N/A 25 IL-27R TRAP (IL-27 antagonist) NP_004834 26 IL-13 AAH96140 27 IL-17 AAC50341 28 IL-33 Isoform a NP_001300974 29 IL-33 Isoform a NP_001300973 30 IL-33 Isoform b NP_001186569 31 IL-33 Isoform c NP_001186570 32 IL-33 Isoform d NP_001300975; NP_001300976 33 IL-33 Isoform e NP_001300977 34 IFN-gamma AAB59534 35 secreted flagellin N/A 36 anti-CTLA4 (CTLA-4 antagonist N/A antibody) 38 Interleukin-2 (IL-2) (murine) NM_008366.3 39 Xc11 (murine) GenBank: BC062249.1 42 4-1BBL (TNFSF9) (murine) GenBank: BC138767.1 55 IL-15R.alpha. N/A 58 h.alpha.CTLA4 N/a com1-19 Anti-PD-1 (PD-1 antagonist antibody) Anti-PD-L1 (PD-L1 antagonist antibody) Anti-TIGIT (TIGIT antagonist antibody) Anti-TGF.beta. (TGF.beta. antagonist antibody) Anti-IL6R (IL-6 receptor antibody)

[0081] Additional detail about the above-discussed agonists that can be expressed from an adenovirus vector as described herein is provided below: GITR Ligand.

[0082] In one embodiment, the heterologous gene is a GITR ligand family gene, such as TNFSF18 (also known as GITRL) (See, e.g., Tone, M., Tone, Y., Adams, E., Yates, S. F., Frewin, M. R., Cobbold, S. P., & Waldmann, H. (2003). Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proceedings of the National Academy of Sciences of the United States of America, 100(25), 15059-15064. doi:10.1073/pnas.2334901100). The GITR/GITRL signaling pathway is associated with activation of immune cells Nocentini, G., Ronchetti, S., Petrillo, M. G., & Riccardi, C. (2012). Pharmacological modulation of GITRL/GITR system: therapeutic perspectives. British Journal of Pharmacology, 165(7), 2089-99. doi:10.1111/j.1476-5381.2011.01753.x). Specifically, the GITRL protein has an immunomodulatory activity including inhibiting the suppressive activity of T regulatory cells and activation of T effector cells. The intratumoral localization of effective amounts of GITRL protein results in stimulation of the immune system and inhibition of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, the costimulatory activity of GITRL protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting from activation and/or recruitment of the immune system to the tumor and enhanced antigen presentation IL-10 Trap.

[0083] In one embodiment, the heterologous gene is an engineered IL-10 trap, such as IL-10 receptor fused to a human immunoglobulin Fc domain. Examples include IL10RA-Fc fusion protein or IL10RA-IL10RB-Fc fusion protein. (See, e.g., Economides, A. N., Carpenter, L. R., Rudge, J. S., Wong, V., Koehler-Stec, E. M., Hartnett, C., . . . Stahl, N. (2003). Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nature Medicine, 9(1), 47-52. doi:10.1038/nm811). The IL-10 family is associated with inhibition of inflammatory response in immune cells through inhibition of the expression of proinflammatory cytokines and co-stimulatory molecules. Expression of IL-10 by T regulatory cells suppresses the activity of T effector cells (Mosser D M, Zhang X. Immunol Rev. 2008 December; 226:205-18. Interleukin-10: new perspectives on an old cytokine). Specifically, the IL-10 trap protein has an immunomodulatory activity by inhibiting the anti-inflammatory activity of IL-10. The intratumoral localization of effective amounts of IL-10 trap protein results in stimulation of the immune system and inhibition of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, IL-10 trap protein inhibition of IL-10's anti-inflammatory activity has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting from activation and/or recruitment of the immune system to the tumor and enhanced antigen presentation. In one embodiment, the IL-10 Receptor Trap includes all or a portion of the extracellular domains of IL-10R.alpha. and IL-10R.alpha..

Anti-CTLA4.

[0084] In one embodiment, the heterologous gene is an antibody (or domain or fragment thereof) that inhibits the function of CTLA4 (See, e.g., Leach D R, Krummel M F, Allison J P Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996 Mar. 22; 271(5256):1734-6.) The CTLA4 family is associated with inhibition of T cells through the interaction with ligands CD80 and CD86 (Krummel M F, Allison J P (1995). "CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation". J. Exp. Med. 182 (2): 459-65.) Specifically, the anti-CTLA4 antibody has an immunomodulatory activity including blocking the inhibitory function of CTLA4 resulting in more efficient activation of T effector cells. The intratumoral localization of effective amounts of anti-CTLA4 antibody results in stimulation of the immune system and inhibition of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, anti-CTLA4 inhibition of CTLA4's T cell inhibitory activity has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting from activation and/or recruitment of the immune system to the tumor and enhanced antigen presentation.

IL-12:

[0085] In one embodiment, the heterologous gene is a member of the Interleukin cytokine family such as IL-12. The IL-12 cytokine family is associated with induction of IFN.gamma. and mediating T-cell dependent immunity. Specifically, IL-12 is an immunostimulatory cytokine with strong antiangiogenic effects. IL-12 has immunomodulatory activity including cell proliferation, lymphocyte differentiation and NK cell activation. The intratumoral localization of effective amounts of IL-12 results in the differentiation, proliferation, and maintenance of T helper 1 (Th1) responses that lead to IFN.gamma. and IL-2 production that in turn, promote T cell responses and macrophage activation. The local expression of effective amounts of IL-12 from intratumoral injections may provide a safety benefit over systemic administration and side effects associated with high IL-12 serum levels. Moreover, the immunostimulatory activity and induction of cytotoxicity mediated by natural killer cells and T cells by IL-12 may have a synergistic effect with the tumor-directed cell-lytic and immune stimulating activity of our adenovirus providing a more effective viral-based therapeutic treatment of human subjects suffering from cancer. In one embodiment, the IL-12 polypeptide is a fusion of IL-12 subunits p35 and p40, linked by a 45 bp linker, including IL-1213:p40 (NM_001303244) and IL-12 Alpha:p35 (NM_008351.1).

GM-CSF:

[0086] In one embodiment, the heterologous gene is a cytokine such as Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony stimulating factor 2 (CSF2). Cytokines are secreted proteins or peptides that mediate and regulate immunity and inflammation. Specifically, GM-CSF has an immunomodulatory activity of functioning as an immune adjuvant and facilitates development of the immune system, acting as a growth factor for DCs and APCs. The localized secretion of effective amounts of GM-CSF results in an increase in dendritic cell (DC) maturation and function as well as macrophage activity, recruiting immune cells to the inflammatory site of tumor treatment, resulting in more effective therapeutic treatment of human subjects suffering from cancer. Moreover, GM-CSF has been demonstrated to be capable of induced long-lasting, specific anti-tumor immunity when combined with cancer vaccines, potentially providing a synergistic effect with the tumor-directed cell-lytic activity of our adenovirus. In a recent phase III clinical trial, an oncolytic herpes simplex virus armed with GM-CSF (T-VEC) showed durable response rates in advanced melanoma patients compared with GM-CSF protein alone.

Secreted Flagellin:

[0087] In one embodiment, the heterologous gene comes from a gram-negative bacterium in the Salmonellae family, such as the gene encoding flagellin. Bacterial proteins, including flagellin, are associated with the activation of the innate immune response, leading to production of proinflammatory cytokines and the up-regulation of costimulatory molecules. Specifically, flagellin is a TLR5 agonist, and binding of secreted flagellin to TLR5 stimulates production of TNF.alpha., and induces infiltration of APC's and TIL's to the local tumor environment. By acting as a strong adjuvant, flagellin is able to prime the immune system to elicit strong adaptive immune responses, resulting in enhanced and broadened immune response a more effective viral-based therapeutic treatment of human subjects suffering from cancer. In some embodiments, secreted Flagellin contains a murine IL-2 signal sequence (See NM_008366) and Salmonella Flagellin, GenBank: D13689.

TNF.alpha. and non-cleavable TNF.alpha..

[0088] In one embodiment, the heterologous gene is an engineered TNF.alpha. ligand family gene, such as a non-cleavable (membrane-bound, transmembrane) form of TNF.alpha. (See, e.g., Li Q, Li L, Shi W, Jiang X, Xu Y, Gong F, Zhou M, Edwards C K 3rd, Li Z., Mechanism of action differences in the antitumor effects of transmembrane and secretory tumor necrosis factor-alpha in vitro and in vivo. Cancer Immunol Immunother. 2006: 55, 1470-9.). TNF.alpha. belongs to a family of pro-inflammatory cytokines (Calcinotto A, Grioni M, Jachetti E, Curnis F, Mondino A, Parmiani G, Corti A, Bellone M. Targeting TNF.alpha. to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J Immunol. 2012; 188: 2687-94.). Specifically, expression of TNF.alpha. in the tumor microenvironment is expected to increase the inflammatory milieu resulting in increased anti-tumor immune responses. Use of a non-cleavable TNF.alpha. results in a tethered form of TNF.alpha. which remains membrane-bound. The intratumoral localization of effective amounts of TNF.alpha. protein results in stimulation of the immune system and inhibition of growth of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. In addition, local expression may provide a safety benefit over systemic administration of TNF.alpha.. Moreover, the immunomodulatory activity of the membrane-bound TNF.alpha. protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting from activation and/or recruitment of the immune system to the tumor and enhanced antigen presentation.

OX40L.

[0089] In one embodiment, the heterologous gene is an OX40L family gene, such as TNFSF4 (also called OX40L, CD252) (See, e.g., Dannull J, Nair S, Su Z, Boczkowski D, DeBeck C, Yang B, Gilboa E, Vieweg J Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand. Blood. 2005, 105: 3206-13.). The TNFSF is associated with activation of immune cells (Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009; 229:173-91.). Specifically, OX40L is a co-stimulatory ligand for TNFRSF4 (OX40, CD134) resulting in activation of T cells. Expression of OX40L in the tumor microenvironment and binding to its cognate receptor (OX40) is expected to increase the activity (proliferation, cytokine release) of tumor infiltrating lymphocytes (TILs) resulting in antitumor activity. The intratumoral localization of effective amounts of OX40L protein results in stimulation of the immune system and inhibition of growth of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Local expression may provide a safety benefit over systemic administration of OX40L. Moreover, the immunomodulatory activity of the OX40L protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting from activation and/or recruitment of the immune system to the tumor and enhanced antigen presentation IL-7.

[0090] In one embodiment, the heterologous gene is an IL-7 cytokine family gene, such as IL-7 (See, e.g., Gao J, Zhao L, Wan Y Y, Zhu B., Mechanism of Action of IL-7 and Its Potential Applications and Limitations in Cancer Immunotherapy. Int J Mol Sci. 2015, 16: 10267-80.). IL-7 belongs to a family of pro-inflammatory cytokines (Geiselhart L A, Humphries C A, Gregorio T A, Mou S, Subleski J, Komschlies K L. IL-7 administration alters the CD4:CD8 ratio, increases T cell numbers, and increases T cell function in the absence of activation. J Immunol. 2001; 166: 3019-27.). Specifically, expression of IL-7 in the tumor microenvironment is expected to increase the inflammatory milieu resulting in increased anti-tumor immune responses. The intratumoral localization of effective amounts of IL-7 protein results in stimulation of the immune system and inhibition of growth of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, the immunomodulatory activity of the IL-7 protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting from activation and/or recruitment of the immune system to the tumor and enhanced antigen presentation.

CD40L

[0091] In one embodiment, the heterologous gene is a member of the TNF superfamily, such as CD40L (also known as CD40LG or CD154) (See, e.g., Hassan G S, et al., 2015. "Role of CD154 in cancer pathogenesis and immunotherapy." Cancer Treat Rev 4 1(5):431-40). The CD40L is the ligand for CD40 expressed on antigen presenting cells. Specifically, the CD40L protein has a costimulatory activity important for activation of T cell dependent immune responses (Sotomayor E M, et al., 1999. "Conversion of tumor-directed CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40." Nat Med. 5:780-787; French R R, et al., 1999. "CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med. 5:548-553). The intratumoral localization of effective amounts of CD40 protein results in activation of the immune system and lysis of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, the costimulatory immunomodulatory activity of CD40 protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting in a local and systemic immune response against the tumor.

IL-15 and IL-15 Hybrid

[0092] In one embodiment, the heterologous gene is a cytokine family gene, such as Interleukin 15 (IL-15) (See, e.g., Di Sabatino A, et. al., 2011 "Role of IL-15 in immune-mediated and infectious diseases". Cytokine Growth Factor Rev. 22 (1): 19-33.; Steel J C, et al., 2012, "Interleukin-15 biology and its therapeutic implications in cancer". Trends Pharmacol. Sci. 33 (1): 35-41). IL-15 is a cytokine that regulates T cell and NK cell activation and proliferation. (Waldmann T A, et al., (1999). "The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens". Annu. Rev. Immunol. 17: 19-49). Specifically, the IL-15 protein has an immunomodulatory activity by providing survival signals to maintain memory T cells in the absence of antigen. IL-15 has also been shown to enhance the anti-tumor immunity of CD8+ T cells (See, Klebanoff C A, et al., "IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T Cells" Proc. Natl. Acad. Sci. USA. 101 (7): 1969-74; and Teague R M, et al., "Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors" Nat. Med. 12 (3): 335-41). Expression of an IL-15 hybrid molecule (IL-15 linked to the IL-15 Receptor alpha, see Tosic et al., PLos ONE 9(10): e109801 (2014)) leads to stabilization and increased bioactivity (Bergamaschi et al., 2008. "Intracellular Interaction of Interleukin-15 with Its Receptor a during Production Leads to Mutual Stabilization and Increased Bioactivity", JBC, 283(7):4189-99; Bergamaschi et al., 2013. "Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ra in human and mouse serum", Blood 120(1):e1). The intratumoral localization of effective amounts of IL-15 protein results in activation of the immune system and lysis of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, the survival signals provided by IL-15 protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting in a local and systemic immune response against the tumor. In some embodiments, an IL-15 hybrid includes IL-15, P2A, and IL-15Ra, IL-15 (NM_008357), 68 bp P2A, and IL-15R.alpha. (GenBank: BC132233.1).

CD70

[0093] In one embodiment, the heterologous gene is a member of the TNF superfamily, such as CD70 (also known as TNFSF7 or CD27L). (See, e.g., Denoeud J and Moser M., 2011. "Role of CD27/CD70 pathway of activation in immunity and tolerance." J Leukoc Biol. 89(2):195-203). CD70 is expressed on activated T and B cells, as well as mature dendritic cells, and acts as a ligand for CD27. CD70 plays a costimulatory role in promoting T cell expansion and differentiation (Keller A M, et al., 2008. "Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity," Immunity 29(6):934-46; Bonehill A, et al., 2008 "Enhancing the T-cell stimulatory capacity of human dendritic cells by co-electroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA," Mol Ther. 16(6):1170-80). In addition, CD70 expression in the tumor microenvironment will increase NK-mediated tumor clearance and promote an adaptive immune response against the tumor (Kelly J M, et al., 2002. "Induction of tumor-directed T cell memory by NK cell-mediated tumor rejection," Nat Immunol. 3(1):83-90). The intratumoral localization of effective amounts of CD70 protein results in activation of the immune system and lysis of the tumor, resulting in more effective viral-based therapeutic treatment of human subjects suffering from cancer. Moreover, the immunomodulatory activity of CD70 protein has a synergistic effect with the tumor-directed cell-lytic activity of the adenovirus, resulting in a local and systemic immune response against the tumor.

[0094] In a specific embodiment, the agonist of a co-stimulatory signal of an immune cell expressed by the adenovirus is an agonist of a co-stimulatory receptor expressed by an immune cell. Specific examples of co-stimulatory receptors that can be expressed by the adenovirus include glucocorticoid-induced tumor necrosis factor receptor (GITR), Inducible T-cell co-stimulator (ICOS or CD278), OX40 (CD134), CD27, CD28, 4-IBB(CD137), CD40, CD226, cytotoxic and regulatory T cell molecule (CRT AM), death receptor 3 (DR3), lymphotoxin-beta receptor (LTBR), transmembrane activator and CAML interactor (TACI), B cell-activating factor receptor (BAFFR), and B cell maturation protein (BCMA). In a specific embodiment, the agonist of a co-stimulatory receptor expressed by an immune cell is an antibody (or an antigen-binding fragment thereof) or ligand that specifically binds to the co-stimulatory receptor. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the antibody is an sc-Fv. In a specific embodiment, the antibody is a bispecific antibody that binds to two receptors on an immune cell. In one embodiment, the bispecific antibody binds to a receptor on an immune cell and to another receptor on a cancer cell. In specific embodiments, the antibody is a human or humanized antibody. In certain embodiments, the ligand or antibody is a chimeric protein.

[0095] In a specific embodiment, the antagonist of an inhibitory signal of an immune cell is an antagonist of an inhibitory receptor expressed by an immune cell. Specific examples of inhibitory receptors include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4 or CD52), programmed cell death protein 1 (PD1 or CD279), B and T-lymphocyte attenuator (BTLA), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), T-cell membrane protein 3 (TIM3), adenosine A2a receptor (A2aR), T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and CD160. In a specific embodiment, the antagonist of an inhibitory receptor expressed by an immune cell is an antibody (or an antigen-binding fragment thereof) that specifically binds to the co-stimulatory receptor.

[0096] Antibodies include, but are not limited to, monoclonal antibodies, bispecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, polyclonal antibodies, single domain antibodies, camelid or camelized antibodies, single-chain Fvs (scFv), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked bispecific Fvs (sdFv), intrabodies, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id and anti-anti-Id antibodies to antibodies), and epitope-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. In a specific embodiment, an antibody is a human or humanized antibody. In another specific embodiment, an antibody is a monoclonal antibody or scFv. In certain embodiments, an antibody is a human or humanized monoclonal antibody or scFv. In other specific embodiments, the antibody is a bispecific antibody. In certain embodiments, the bispecific antibody specifically binds to a co-stimulatory receptor of an immune cell or an inhibitory receptor of an immune, and a receptor on a cancer cell. In some embodiments, the bispecific antibody specifically binds to two receptors immune cells, e.g., two co-stimulatory receptors on immune cells, two inhibitory receptors on immune cells, or one co-stimulatory receptor on immune cells and one inhibitory receptor on immune cells.

[0097] The recombinant AVs described herein may be engineered to express any agonist of a co-stimulatory signal and/or any antagonist of an inhibitory signal of an immune cell, such as, e.g., a T-lymphocyte, NK cell or antigen-presenting cell (e.g., a dendritic cell or macrophage). In specific embodiments, the agonist and/or antagonist is an agonist of a human co-stimulatory signal of an immune cell and/or antagonist of a human inhibitory signal of an immune cell. In certain embodiments, the agonist of a co-stimulatory signal is an agonist of a co-stimulatory molecule (e.g., co-stimulatory receptor) found on immune cells, such as, e.g., T-lymphocytes (e.g., CD4+ or CD8+ T-lymphocytes), NK cells and/or antigen-presenting cells (e.g., dendritic cells or macrophages). Specific examples of co-stimulatory molecules include glucocorticoid-induced tumor necrosis factor receptor (GITR), Inducible T-cell co-stimulator (ICOS or CD278), OX40 (CD134), CD27, CD28, 4-IBB (CD137), CD40, lymphotoxin alpha (LT alpha), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes), CD226, cytotoxic and regulatory T cell molecule (CRT AM), death receptor 3 (DR3), lymphotoxin-beta receptor (LTBR), transmembrane activator and CAML interactor (TACI), B cell-activating factor receptor (BAFFR), and B cell maturation protein (BCMA). In specific embodiments, the agonist is an agonist of a human co-stimulatory receptor of an immune cell. In certain embodiments, the agonist of a co-stimulatory receptor is not an agonist of ICOS. In some embodiments, the antagonist is an antagonist of an inhibitory molecule (e.g., inhibitory receptor) found on immune cells, such as, e.g., T-lymphocytes (e.g., CD4+ or CD8+ T-lymphocytes), NK cells and/or antigen-presenting cells (e.g., dendritic cells or macrophages). Specific examples of inhibitory molecules include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4 or CD52), programmed cell death protein 1 (PD1 or CD279), B and T-lymphocyte attenuator (BTLA), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), T-cell membrane protein 3 (TIM3), CD 160, adenosine A2a receptor (A2aR), T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and CD 160. In specific embodiments, the antagonist is an antagonist of a human inhibitory receptor of an immune cell.

[0098] In a specific embodiment, the agonist of a co-stimulatory receptor is an antibody or antigen-binding fragment thereof that specifically binds to the co-stimulatory receptor. Specific examples of co-stimulatory receptors include GITR, ICOS, OX40, CD27, CD28, 4-1BB, CD40, LT alpha, LIGHT, CD226, CRT AM, DR3, LTBR, TACI, BAFFR, and BCMA. In certain specific embodiments, the antibody is a monoclonal antibody. In other specific embodiments, the antibody is an sc-Fv. In a specific embodiment, the antibody is a bispecific antibody that binds to two receptors on an immune cell. In other embodiments, the bispecific antibody binds to a receptor on an immune cell and to another receptor on a cancer cell. In specific embodiments, the antibody is a human or humanized antibody.

[0099] In another embodiment, the agonist of a co-stimulatory receptor expressed by the adenovirus is a ligand of the co-stimulatory receptor. In certain embodiments, the ligand is fragment of a native ligand. Specific examples of native ligands include ICOSL, B7RP1, CD137L, OX40L, CD70, herpes virus entry mediator (HVEM), CD80, and CD86. The nucleotide sequences encoding native ligands as well as the amino acid sequences of native ligands are known in the art. For example, the nucleotide and amino acid sequences of B7RP1 (otherwise known as ICOSL; GenBank human: NM_015259.4, NP_056074.1 murine: NM_015790.3, NP_056605.1), CD137L(GenBank human: NM_003811.3, NP_003802.1, murine: NM_009404.3, NP_033430.1), OX40L(GenBank human: NM_003326.3, NP_003317.1, murine: NM_009452.2, NP_033478.1), CD70(GenBank human: NM_001252.3, NP_001243.1, murine: NM_011617.2, AAD00274.1), CD80(GenBank human: NM_005191.3, NP_005182.1, murine: NM_009855.2, NP_033985.3), and CD86 (GenBank human: NM_005191.3, CAG46642.1, murine: NM_019388.3, NP_062261.3) can be found in GenBank. In other embodiments, the ligand is a derivative (e.g., a fragment, domain, fusion, or other modification of a full-length polypeptide) a native ligand. In some embodiments, the ligand is a fusion protein comprising at least a portion of the native ligand or a derivative of the native ligand that specifically binds to the co-stimulatory receptor, and a heterologous amino acid sequence. In specific embodiments, the fusion protein comprises at least a portion of the native ligand or a derivative of the native ligand that specifically binds to the co-stimulatory receptor, and the Fc portion of an immunoglobulin or a fragment thereof. An example of a ligand fusion protein is a 4-IBB ligand fused to Fc portion of immunoglobulin (described by Meseck M et al., J Immunother. 2011 34: 175-82).

[0100] In another embodiment, the antagonist of an inhibitory receptor expressed by the adenovirus is an antibody (or an antigen-binding fragment) or a soluble receptor that specifically binds to the native ligand for the inhibitory receptor and blocks the native ligand from binding to the inhibitory receptor and transducing an inhibitory signal(s). Specific examples of native ligands for inhibitory receptors include PDL-1, PDL-2, B7-H3, B7-H4, HVEM, Gal9 and adenosine. Specific examples of inhibitory receptors that bind to a native ligand include CTLA-4, PD-1, BTLA, KIR, LAG3, TIM3, and A2aR.

[0101] In specific embodiments, the antagonist of an inhibitory receptor expressed by the adenovirus is a soluble receptor that specifically binds to the native ligand for the inhibitory receptor and blocks the native ligand from binding to the inhibitory receptor and transducing an inhibitory signal(s). In certain embodiments, the soluble receptor is a fragment of a native inhibitory receptor or a fragment of a derivative of a native inhibitory receptor that specifically binds to native ligand {e.g., the extracellular domain of a native inhibitory receptor or a derivative of an inhibitory receptor). In some embodiments, the soluble receptor is a fusion protein comprising at least a portion of the native inhibitory receptor or a derivative of the native inhibitory receptor (e.g., the extracellular domain of the native inhibitory receptor or a derivative of the native inhibitory receptor), and a heterologous amino acid sequence. In specific embodiments, the fusion protein comprises at least a portion of the native inhibitory receptor or a derivative of the native inhibitory receptor, and the Fc portion of an immunoglobulin or a fragment thereof. An example of a soluble receptor fusion protein is a LAG3-Ig fusion protein (described by Huard B et al, Eur J Immunol (1995) 25:2718-21).

[0102] In specific embodiments, the antagonist of an inhibitory receptor expressed by the adenovirus is an antibody (or an antigen-binding fragment) that specifically binds to the native ligand for the inhibitory receptor and blocks the native ligand from binding to the inhibitory receptor and transducing an inhibitory signal(s). In certain specific embodiments, the antibody is a monoclonal antibody. In other specific embodiments, the antibody is an scFv. In particular embodiments, the antibody is a human or humanized antibody. A specific example of an antibody to inhibitory ligand is anti-PD-L1 antibody (Iwai Y, et al. PNAS 2002; 99: 12293-12297).

[0103] In another embodiment, the antagonist of an inhibitory receptor expressed by the adenovirus is an antibody (or an antigen-binding fragment) or ligand that binds to the inhibitory receptor, but does not transduce an inhibitory signal(s). Specific examples of inhibitory receptors include CTLA-4, PD1, BTLA, TIGIT, KIR, LAG3, TIM3, and A2aR. In certain specific embodiments, the antibody is a monoclonal antibody. In other specific embodiments, the antibody is an scFv. In particular embodiments, the antibody is a human or humanized antibody. A specific example of an antibody to inhibitory receptor is anti-CTLA-4 antibody (Leach D R, et al. Science 1996; 271: 1734-1736). Another example of an antibody to inhibitory receptor is anti-PD-1 antibody (Topalian S L, NEJM 2012; 28:3167-75).

[0104] In certain embodiments, a chimeric adenovirus described herein is engineered to produce an antagonist of CTLA-4, such as, e.g., ipilimumab or tremelimumab. In certain embodiments, a chimeric adenovirus described herein is engineered to an antagonist of PD1, such as, e.g., MDX-1106 (BMS-936558), MK3475, CT-011, AMP-224, or MDX-1105. In certain embodiments, a chimeric adenovirus described herein is engineered to express an antagonist of LAG3, such as, e.g., IMP321. In certain embodiments, a chimeric adenovirus described herein is engineered to express an antibody (e.g., a monoclonal antibody or an antigen-binding fragment thereof, or scFv) that binds to B7-H3, such as, e.g., MGA271. In specific embodiments, a chimeric adenovirus described herein is engineered to express an agonist of a co-stimulatory signal of an immune cell and/or an antagonist of an inhibitory signal of an immune cell. In specific embodiments, adenovirus described herein is engineered to express anti-CD28 scFv, ICOSL, CD40L, OX40L, CD137L, GITRL, and/or CD70.

[0105] In certain embodiments, an agonist of a co-stimulatory signal of an immune cell expressed by the adenovirus induces (e.g., selectively) induces one or more of the signal transduction pathways induced by the binding of a co-stimulatory receptor to its ligand. In specific embodiments, an agonist of a co-stimulatory receptor induces one or more of the signal transduction pathways induced by the binding of the co-stimulatory receptor to one or more of its ligands by at least 25%, 30%, 40%>, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, or in the range of between 25% to 50%, 25% to 75%, 50% to 75%, 50% to 95%, 75% to 95%, or 75% to 100% relative to the one or more signal transduction pathways induced by the binding of the co-stimulatory receptor to one or more of its ligands in the absence of the agonist. In specific embodiments, an agonist of a co-stimulatory receptor: (i) induces one or more of the signal transduction pathways induced by the binding of the co-stimulatory receptor to one particular ligand by at least 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, or in the range of between 25% to 50%, 25% to 75%, 50% to 75%, 50% to 95%, 75% to 95%, or 75% to 100% relative to the one or more signal transduction pathways induced by the binding of the co-stimulatory receptor to the particular ligand in the absence of the agonist; and (ii) does not induce, or induces one or more of the signal transduction pathways induced by the binding of the co-stimulatory receptor to one or more other ligands by less than 20%, 15%, 10%, 5%, or 2%, or in the range of between 2% to 5%, 2% to 10%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 15%, or 15% to 20% relative to the one or more signal transduction pathways induced by the binding of the co-stimulatory receptor to such one or more other ligands in the absence of the agonist.

[0106] In certain embodiments, an agonist of a co-stimulatory signal of an immune cell activates or enhances (e.g., selectively activates or enhances) one or more of the signal transduction pathways induced by the binding of a co-stimulatory receptor to its ligand. In specific embodiments, an agonist of a co-stimulatory receptor activates or enhances one or more of the signal transduction pathways induced by the binding of the co-stimulatory receptor to one or more of its ligands by at least 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, or in the range of between 25% to 50%, 25% to 75%, 50% to 75%, 50% to 95%, 75% to 95%), or 75%) to 100% relative to the one or more signal transduction pathways induced by the binding of co-stimulatory receptor to one or more of its ligands in the absence of the agonist. In specific embodiments, an agonist of a co-stimulatory receptor: (i) an agonist of a co-stimulatory signal activates or enhances one or more of the signal transduction pathways induced by the binding of the co-stimulatory receptor to one particular ligand by at least 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, or in the range of between 25% to 50%, 25% to 75%, 50% to 75%, 50% to 95%, 75% to 95%, or 75% to 100% relative to the one or more signal transduction pathways induced by the binding of the co-stimulatory receptor to the particular ligand in the absence of the agonist; and (ii) does not activate or enhance, or activates or enhances one or more of the signal transduction pathways induced by the binding of the co-stimulatory receptor to one or more other ligands by less than 20%, 15%, 10%, 5%, or 2%, or in the range of between 2% to 5%, 2% to 10%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 15%, or 15% to 20% relative to the one or more signal transduction pathways induced by the binding of the co-stimulatory receptor to such one or more other ligands in the absence of the agonist.

[0107] In some embodiments, an antagonist of an inhibitory signal of an immune cell (e.g., selectively) inhibits or reduces one or more of the signal transduction pathways induced by the binding of an inhibitory receptor to its ligand. In specific embodiments, an antagonist of an inhibitory receptor inhibits or reduces one or more of the signal transduction pathways induced by the binding of the inhibitory receptor to one or more of its ligands by at least 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, or in the range of between 25% to 50%, 25% to 75%, 50% to 75%, 50% to 95%, 75% to 95%, or 75% to 100% relative to the one or more signal transduction pathways induced by the binding of the inhibitory receptor to one or more of its ligands in the absence of the antagonist. In specific embodiments, an antagonist of an inhibitory receptor: (i) inhibits or reduces one or more of the signal transduction pathways induced by the binding of the inhibitory receptor to one particular ligand by at least 25%, 30%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%, or in the range of between 25% to 50%, 25% to 75%, 50% to 75%, 50% to 95%, 75% to 95%, or 75% to 100% relative to the one or more signal transduction pathways induced by the binding of the inhibitory receptor to the one particular ligand in the absence of the antagonist; and (ii) does not inhibit or reduce, or inhibits or reduces one or more of the signal transduction pathways induced by the binding of the inhibitory receptor to one or more other ligands by less than 20%, 15%, 10%, 5%, or 2%, or in the range of between 2% to 5%, 2% to 10%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 15%, or 15% to 20% relative to the one or more signal transduction pathways induced by the binding of inhibitory receptor to such one or more other ligands in the absence of the antagonist.

[0108] In specific embodiments, an agonist of a co-stimulatory signal of an immune cell and/or an antagonist of an inhibitory signal of an immune cell induces, activates and/or enhances one or more immune activities, functions or responses. The one or more immune activities, functions or responses can be in the form of, e.g., an antibody response (humoral response) or a cellular immune response, e.g., cytokine secretion (e.g., interferon-gamma), helper activity or cellular cytotoxicity. In one embodiment, expression of an activation marker on immune cells (e.g., CD44, Granzyme, or Ki-67), expression of a co-stimulatory receptor on immune cells (e.g., ICOS, CD28, OX40, or CD27), expression of a ligand for a co-stimulatory receptor (e.g., B7HRP1, CD80, CD86, OX40L, or CD70), cytokine secretion, infiltration of immune cells (e.g., T-lymphocytes, B lymphocytes and/or NK cells) to a tumor, antibody production, effector function, T cell activation, T cell differentiation, T cell proliferation, B cell differentiation, B cell proliferation, and/or NK cell proliferation is induced, activated and/or enhanced following contact with an agonist of a co-stimulatory signal of an immune cell and/or an antagonist of an inhibitory signal of an immune cell. In another embodiment, myeloid-derived suppressor cell (MDSC) tumor infiltration and proliferation, Treg tumor infiltration, activation and proliferation, peripheral blood MDSC and Treg counts are inhibited following contact with an agonist of a co-stimulatory signal of an immune cell and/or an antagonist of an inhibitory signal of an immune cell.

[0109] In certain embodiments, a chimeric adenovirus described herein is engineered to produce two or more immunomodulatory polypeptides. In some embodiments, the chimeric adenovirus produces a first immunomodulatory polypeptide and a second immunomodulatory polypeptide.

[0110] For example, a first immunomodulatory polypeptide is a costimulatory ligand, a proinflammatory cytokine, an inhibitor of an inhibitory cytokine, an initiator of a localized immune response, an inhibitor of a co-inhibitory checkpoint molecule, or a ligand of a cluster of differentiation (CD) molecule, and the second immunomodulatory polypeptide is a costimulatory ligand, a proinflammatory cytokine, an inhibitor of an inhibitory cytokine, an initiator of a localized immune response, an inhibitor of a co-inhibitory checkpoint molecule, or a ligand of a cluster of differentiation (CD) molecule.

[0111] For example, a first immunomodulatory polypeptide is a costimulatory ligand, and the second immunomodulatory polypeptide is a costimulatory ligand.

[0112] For another example, a first immunomodulatory polypeptide is a costimulatory ligand and the second immunomodulatory polypeptide is a pro-inflammatory cytokine.

[0113] In some embodiments, two or more immunomodulatory polypeptides are expressed from a single transcript. To express two or more proteins from a single transcript determined by a viral or non-viral vector, an internal ribosome entry site (IRES) sequence is commonly used to drive expression of the second, third, fourth coding sequence, etc. When two coding sequences are linked via an IRES, the translational expression level of the second coding sequence is often significantly reduced (Furler et al. 2001. Gene Therapy 8:864-873). In fact, the use of an IRES to control transcription of two or more coding sequences operably linked to the same promoter can result in lower level expression of the second, third, etc. coding sequence relative to the coding sequence adjacent the promoter. In addition, an IRES sequence may be sufficiently long to impact complete packaging of the vector, e.g., the eCMV IRES has a length of 507 base pairs.

[0114] Internal ribosome entry site (IRES) elements were first discovered in picornavirus mRNAs (Jackson et al. 1990. Trends Biochem. Sci. 15:477-83) and Jackson and Kaminski, RNA (1995) 1:985-1000). Examples of IRES generally employed by those of skill in the art include those referenced in Table I and Appendix A, as well as those described in U.S. Pat. No. 6,692,736. Examples of "IRES" known in the art include, but are not limited to IRES obtainable from picornavirus (Jackson et al., 1990) and IRES obtainable from viral or cellular mRNA sources, such as for example, immunoglobulin heavy-chain binding protein (BiP), the vascular endothelial growth factor (VEGF) (Huez et al. 1998, Mol. Cell. Biol. 18:6178-6190), the fibroblast growth factor 2 (FGF-2), and insulin-like growth factor (IGFII), the translational initiation factor eIF4G and yeast transcription factors TFIID and HAP4, the encephelomyocarditis virus (EMCV) which is commercially available from Novagen (Duke et al. 1992. J. Virol 66:1602-9) and the VEGF IRES (Huez et al. 1998. Mol. Cell. Biol. 18:6178-90). IRES have also been reported in different viruses such as cardiovirus, rhinovirus, aphthovirus, HCV, Friend murine leukemia virus (FrMLV) and Moloney murine leukemia virus (MoMLV). As used herein, "IRES" encompasses functional variations of IRES sequences as long as the variation is able to promote direct internal ribosome entry to the initiation codon of a cistron. An IRES may be mammalian, viral or protozoan. The IRES promotes direct internal ribosome entry to the initiation codon of a downstream cistron, leading to cap-independent translation. Thus, the product of a downstream cistron can be expressed from a bicistronic (or multicistronic) mRNA, without requiring either cleavage of a polyprotein or generation of a monocistronic mRNA. Internal ribosome entry sites are approximately 450 nucleotides in length and are characterized by moderate conservation of primary sequence and strong conservation of secondary structure. The most significant primary sequence feature of the IRES is a pyrimidine-rich site whose start is located approximately 25 nucleotides upstream of the 3' end of the IRES. See Jackson et al. (1990). Three major classes of picornavirus IRES have been identified and characterized: the cardio- and aphthovirus class (for example, the encephalomyocarditis virus, Jang et al. 1990. Gene Dev 4:1560-1572); the entero- and rhinovirus class (for example, polioviruses, Borman et al. 1994. EMBO J. 13:3149-3157); and the hepatitis A virus (HAV) class, Glass et al. 1993. Virol 193:842-852). For the first two classes, two general principles apply. First, most of the 450-nucleotide sequence of the IRES functions to maintain particular secondary and tertiary structures conducive to ribosome binding and translational initiation. Second, the ribosome entry site is an AUG triplet located at the 3' end of the IRES, approximately 25 nucleotides downstream of a conserved oligopyrimidine tract. Translation initiation can occur either at the ribosome entry site (cardioviruses) or at the next downstream AUG (entero/rhinovirus class). Initiation occurs at both sites in aphthoviruses. HCV and pestiviruses such as bovine viral diarrhea virus (BVDV) or classical swine fever virus (CSFV) have 341 nt and 370 nt long 5'-UTR respectively. These 5'-UTR fragments form similar RNA secondary structures and can have moderately efficient IRES function (Tsukiyama-Kohara et al. 1992. J. Virol. 66:1476-1483; Frolov et al. 1998. RNA 4:1418-1435). Recent studies showed that both Friend-murine leukemia virus (MLV) 5'-UTR and rat retrotransposon virus-like 30S (VL30) sequences contain IRES structure of retroviral origin (Torrent et al. 1996. Hum. Gene Ther 7:603-612). In eukaryotic cells, translation is normally initiated by the ribosome scanning from the capped mRNA 5' end, under the control of initiation factors. However, several cellular mRNAs have been found to have IRES structure to mediate the cap-independent translation (van der Velde, et al. 1999. Int J Biochem Cell Biol. 31:87-106). Examples of IRES elements include, without limitation, immunoglobulin heavy-chain binding protein (BiP) (Macejak et al. 1991. Nature 353:90-94), antennapedia mRNA of Drosophila (Oh et al. 1992. Gene and Dev 6:1643-1653), fibroblast growth factor-2 (FGF-2) (Vagner et al. 1995. Mol. Cell. Biol. 15:35-44), platelet-derived growth factor B (PDGF-B) (Bernstein et al. 1997. J. Biol. Chem. 272:9356-9362), insulin-like growth factor II (Teerink et al. (1995) Biochim. Biophys. Acta 1264:403-408), and the translation initiation factor eIF4G (Gan et al. 1996. J. Biol. Chem. 271:623-626). Recently, vascular endothelial growth factor (VEGF) was also found to have IRES element (Stein et al. 1998. Mol. Cell. Biol. 18:3112-3119; Huez et al. 1998. Mol. Cell. Biol. 18:6178-6190). Further examples of IRES sequences include Picornavirus HAV (Glass et al. 1993. Virology 193:842-852); EMCV (Jang and Wimmer. 1990. Gene Dev. 4:1560-1572); Poliovirus (Borman et al. 1994. EMBO J. 13:3149-3157); HCV (Tsukiyama-Kohara et al. 1992. J. Virol. 66:1476-1483); pestivirus BVDV (Frolov et al. 1998. RNA. 4:1418-1435); Leishmania LRV-1 (Maga et al. 1995. Mol. Cell. Biol. 15:4884-4889); Retroviruses: MoMLV (Torrent et al. 1996. Hum. Gene Ther. 7:603-612). VL30, Harvey murine sarcoma virus, REV (Lopez-Lastra et al. 1997. Hum. Gene Ther. 8:1855-1865). IRES may be prepared using standard recombinant and synthetic methods known in the art. For cloning convenience, restriction sites may be engineered into the ends of the IRES fragments to be used.

[0115] In some embodiments, two immunomodulatory polypeptides are expressed from separate transcripts, i.e., a first transcript and a second transcript. In some embodiments, the two transcripts are encoded by a DNA insertion at the same location in the adenovirus, e.g., both inserted in E1b, E3, or E4. In some embodiments, the two transcripts are encoded by a DNA insertion at the different locations in the adenovirus, e.g., a first transcript DNA inserted in E1b and a second transcript DNA inserted in E3 or E4, or alternatively, a first transcript DNA inserted in E3 and a second transcript DNA inserted in E4.

[0116] Another aspect of the invention provides a virus for causing expression in a target cell of a plurality of recombinant immunomodulatory polypeptides or other protein(s) or polypeptides of interest, wherein the vector also includes a promoter operably linked to a first coding sequence for a first recombinant immunomodulatory polypeptide, a self-processing or other cleavage coding sequence, such as a 2A or 2A-like sequence or a protease recognition site, and a second coding sequence for a second recombinant immunomodulatory polypeptide, wherein the self-processing cleavage sequence or protease recognition site coding sequence is inserted between the first and the second coding sequences. In a related embodiment, the viral vector comprises an expression vector as described above wherein the expression vector further comprises an additional proteolytic cleavage site between the first and second recombinant immunomodulatory polypeptides. A preferred additional proteolytic cleavage site is a furin cleavage site with the consensus sequence RXR/K-R.

Interaction of Oncolytic Activity and Immunomodulatory Activity.

[0117] Oncolytic viruses (OVs) were originally conceived as simply a means of targeted destruction of cancer cells. However, it is now thought that the most effective OV therapies will be those that combine tumor cell death with the stimulation of a host anti-tumor immune response. OVs engineered to express particular immunomodulatory cytokines in tumor cells will be able to specifically guide the immune system toward combating cancer cells. Combining the expression of these cytokines with the release of tumor-associated antigens (TAAs, i.e. tumor cell debris) upon viral lysis of cancer cells will allow for the development of cellular or antibody-mediated anti-tumor immune responses (Lichty et al., 2014, Nature Reviews Cancer, 14: 559-567).

Pharmaceutical Compositions.

[0118] A pharmaceutical composition of the invention comprises at least one of the vectors of the invention as described herein. Furthermore, the composition may comprise at least two, three or four different (i.e., expressing different transgenes) vectors of the invention. In addition to the vector, a pharmaceutical composition may also comprise any other vectors, such as other adenoviral vectors, other therapeutically effective agents, any other agents such as pharmaceutically acceptable carriers, buffers, excipients, adjuvants, antiseptics, filling, stabilizing or thickening agents, and/or any components, e.g., such as components found in corresponding viral or pharmaceutical products.

[0119] The vector(s) described herein can be administered (e.g., in a pharmaceutical composition) to any human or animal, including but not limited to a human or non-human animal having or diagnosed with cancer. According to one embodiment, the cancer is nasopharyngeal cancer, synovial cancer, hepatocellular cancer, renal cancer, cancer of connective tissues, melanoma, lung cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, brain cancer, throat cancer, oral cancer, liver cancer, bone cancer, pancreatic cancer, choriocarcinoma, gastrinoma, pheochromocytoma, prolactinoma, T-cell leukemia/lymphoma, neuroma, von Hippel-Lindau disease, Zollinger-Ellison syndrome, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, ureter cancer, brain cancer, oligodendroglioma, neuroblastoma, meningioma, spinal cord tumor, bone cancer, osteochondroma, chondrosarcoma, Ewing's sarcoma, cancer of unknown primary site, carcinoid, carcinoid of gastrointestinal tract, fibrosarcoma, breast cancer, Paget's disease, cervical cancer, colorectal cancer, rectal cancer, esophagus cancer, gall bladder cancer, head cancer, eye cancer, neck cancer, kidney cancer, Wilms' tumor, liver cancer, Kaposi's sarcoma, prostate cancer, lung cancer, testicular cancer, Hodgkin's disease, non-Hodgkin's lymphoma, oral cancer, skin cancer, mesothelioma, multiple myeloma, ovarian cancer, endocrine pancreatic cancer, glucagonoma, pancreatic cancer, parathyroid cancer, penis cancer, pituitary cancer, soft tissue sarcoma, retinoblastoma, small intestine cancer, stomach cancer, thymus cancer, thyroid cancer, trophoblastic cancer, hydatidiform mole, uterine cancer, endometrial cancer, vagina cancer, vulva cancer, acoustic neuroma, mycosis fungoides, insulinoma, carcinoid syndrome, somatostatinoma, gum cancer, heart cancer, lip cancer, meninges cancer, mouth cancer, nerve cancer, palate cancer, parotid gland cancer, peritoneum cancer, pharynx cancer, pleural cancer, salivary gland cancer, tongue cancer, tonsil cancer. The vector or pharmaceutical composition of the invention may be administered to any eukaryotic subject selected from a group consisting of animals and human beings, in a preferred embodiment of the invention, the subject is a human or a non-human animal. An animal may be selected from a group consisting of pets, domestic animals and production animals.

[0120] The adenoviral vector(s) of the present invention may be administered to a subject, preferably suspended in a biologically compatible solution or pharmaceutically acceptable delivery vehicle. A suitable vehicle includes sterile saline. Other aqueous and non-aqueous isotonic sterile injection solutions and aqueous and non-aqueous sterile suspensions known to be pharmaceutically acceptable carriers and well known to those of skill in the art may be employed for this purpose.

[0121] The therapeutic of the present invention may also be administered directly to the tumor in the form of a liquid, gel or suspension introduced by intratumoral injection. A study examining the treatment of mice bearing subcutaneous human pancreatic adenocarcinoma xenografts with recombinant Newcastle disease virus (rNDV) showed that intratumoral injection yielded better tumor regression than intravenous injection. In this study, animals were injected intratumorally every other day for a total of 4 injections, each containing 5.times.10.sup.7 50% Tissue Culture Infective Dose (TCID50) rNDV in 50 .mu.l (Buijs et al., 2015, Viruses, 6: 2980-2998). Similarly, another study examining the treatment of mice bearing subcutaneous bladder cancer xenografts with modified oncolytic adenovirus found that intratumoral injection significantly suppressed tumor growth. In this study, animals were injected intratumorally twice at a 1-day interval with 5.times.10.sup.8 infectious unit (IFU) viruses in 100 .mu.l (Yang et al., 2015, Cell Death and Disease, e1760). Shown to be well-tolerated in Phase 1 trials, Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus has been examined as an intratumorally-administered treatment for patients with advanced hepatocellular carcinoma (HCC). In this study design, patients were to be injected intratumorally 3 times every 2 weeks at one of 2 dose levels: 1.times.10.sup.8 plaque forming units (pfu), or 1.times.10.sup.9 pfu (Walther and Stein, 2015, Methods in Molecular Biology, 1317: 343-357).

[0122] A single administration of oncolytic adenoviral vectors of the invention may have therapeutic effects. However, in some embodiments of the invention, oncolytic adenoviral vectors or pharmaceutical compositions are administered several times during the treatment period. Oncolytic adenoviral vectors or pharmaceutical compositions may be administered for example from 1 to 10 times in the first 2 weeks, 4 weeks, monthly or during the treatment period. In one embodiment of the invention, administration is done three to seven times in the first 2 weeks, then at 4 weeks and then monthly, in a specific embodiment of the invention, administration is done four times in the first 2 weeks, then at 4 weeks and then monthly. The length of the treatment period may vary, and for example may last from two to 12 months or more.

[0123] To improve the efficacy of the present invention, in some embodiments, the therapeutic of the present invention is administered with an adjuvant. Suitable adjuvants include aluminum salts (alum) such as aluminum hydroxide, aluminum phosphate, and aluminum sulfate, Incomplete Freund's Adjuvant (IFA), and monophosphoryl lipid A (MPL). These adjuvants are suitable for human administration, either alone or optionally all combinations thereof (Chang et al., "Adjuvant Activity of Incomplete Freund's Adjuvant," Adv Drug Deliv Rev 32:173-186 (1998), which is hereby incorporated by reference in its entirety). Other adjuvants include cytokines, such as interleukins (IL-1, IL-2, and IL-12), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), di- and tri-palmitoyl-S-glyceryl cysteine (Pam.sub.2Cys and Pam.sub.3Cys, respectively), a TLR2 agonist, an anti-granulocyte macrophage colony-stimulating factor (GM-CSF) antibody, RR-XS15, Montanide.RTM., and MALP-2.

[0124] The adenoviral vector of the present invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid (e.g., aqueous) form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0125] The therapeutic of the present invention may be orally administered, for example, with an inert diluent, or with a suitable edible carrier, or they may be enclosed in hard or soft-shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the therapeutic may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Various other materials may be present as coatings or to modify the physical form of the dosage unit.

[0126] The therapeutic may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0127] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0128] The therapeutic of the present invention may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[0129] The therapeutic of this invention may be administered in sufficient amounts to transfect the desired cells and provide sufficient levels of integration and expression of the replicating virus to provide a therapeutic benefit without undue adverse effects or with medically acceptable physiological effects which can be determined by those skilled in the medical arts.

[0130] Dosages of the therapeutic will depend primarily on factors, such as the condition being treated, the age, weight, and health of the patient, and may thus vary among patients. The dosage will be adjusted to balance the therapeutic benefit against any viral toxicity or side effects.

[0131] The present invention also relates to a method of enhancing the delivery to and distribution within a tumor mass of therapeutic proteins expressed from viruses. For example, an adenovirus as described herein, optionally in a pharmaceutical composition as described herein, can be injected into a tumor mass such that the virus infects and lyses one or more tumor cell.

Combination Therapy.

[0132] The viral immunotherapy of the invention is effective alone, but combination of multiple adenoviral immunotherapies, or one or more adenoviral immunotherapies with any other therapies, such as traditional therapy, may be more effective than either one alone. For example, each agent of the combination therapy may work independently in the tumor tissue, the adenoviral vectors may sensitize cells to chemotherapy or radiotherapy and/or chemotherapeutic agents may enhance the level of virus replication or effect the receptor status of the target cells. The agents of combination therapy may be administered simultaneously or sequentially.

[0133] In a preferred embodiment of the invention, the method or use further comprises administration of concurrent radiotherapy to a subject. In another preferred embodiment of the invention, the method or use further comprises administration of concurrent chemotherapy to a subject. As used herein "concurrent" refers to a therapy, which has been administered before, after or simultaneously with the gene therapy of the invention. The period for a concurrent therapy may vary from minutes to several weeks. In some embodiments, the concurrent therapy lasts for some hours.

[0134] Agents suitable for combination therapy include but are not limited to afatinib, all-trans retinoid acid, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, 5-fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, temozolomide, teniposide, tioguanine, valrubicin, vinblastine, vincristine, vindesine and vinorelbine.

[0135] In some embodiments, the method or use further comprises administration of verapamil or another calcium channel blocker to a subject. "Calcium channel blocker" refers to a class of drugs and natural substances which disrupt the conduction of calcium channels, and if may be selected from a group consisting of verapamil, dihydropyridines, gallopamil, diltiazem, mibefradil, bepridil, fluspirilene and fendiline.

[0136] In some embodiments, the method or use further comprises administration of autophagy inducing agents to a subject. Autophagy refers to a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. "Autophagy inducing agents" refer to agents capable of inducing autophagy and may be selected from a group consisting of, but not limited to, mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus, and ridaforolimus), P13K inhibitors (e.g., wortmannin, lithium, tamoxifen, chloroquine, bafilomycin, and temozolomide. In a specific embodiment of the invention, the method further comprises administration of temozolomide to a subject. Temozolomide may be either oral or intravenous temozolomide.

[0137] In some embodiments, the method or use further comprises administration of chemotherapy or anti-CD20 therapy or other approaches for blocking of neutralizing antibodies. "Anti-CD20 therapy" refers to agents capable of killing CD20 positive cells, and may be selected from a group consisting of rituximab and other anti-CD20 monoclonal antibodies. "Approaches for blocking of neutralizing antibodies" refers to agents capable of inhibiting the generation of anti-viral antibodies that normally result from infection and may be selected from a group consisting of different chemotherapeutics, immunomodulatory substances, corticoids and other drugs. These substances may be selected from a group consisting of, but not limited to, cyclophosphamide, ciclosporin, azathioprine, methylprednisolone, etoposide, CD40L, CTLA4, FK506 (tacrolimus), IL-12, IFN-.gamma., interleukin 10, anti-CD8, anti-CD4 antibodies, hematopoietic stem cell transplantation (HSCT) and oral adenoviral proteins.

[0138] In some embodiments, the oncolytic adenoviral vector of the invention induces virion-mediated oncolysis of tumor cells and activates human immune response against tumor cells. In some embodiments, the method or use further comprises administration of substances capable to downregulating regulatory T-cells in a subject in an amount to downregulate (e.g., by at least 10%, 20%, 50%, 70%, 90% or more) regulatory T-cells in the subject. "Substances capable to downregulating regulatory T-cells" refers to agents that reduce the numbers of cells identified as T-suppressor or Regulatory T-cells. These cells have been identified as consisting one or many of the following immunophenotypic markers: CD4+, CD25+, FoxP3+, CD127- and GITR+. Such agents reducing T-suppressor or Regulatory T-cells may be selected from a group consisting of anti-CD25 antibodies or chemotherapeutics.

[0139] In some embodiments, the method or use further comprises administration of cyclophosphamide to a subject. Cyclophosphamide is a common chemotherapeutic agent, which has also been used in some autoimmune disorders. In the present invention, cyclophosphamide can be used to enhance viral replication and the effects of GM-CSF induced stimulation of NK and cytotoxic T-cells for enhanced immune response against the tumor. It can be used as intravenous bolus doses or low-dose oral metronomic administration.

Kits

[0140] The invention further relates to pharmaceutical packs and kits comprising one or more containers filled with one or more of the ingredients of the aforementioned compositions of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, reflecting approval by the agency of the manufacture, use or sale of the product for human administration.

EXAMPLES

[0141] The present invention is further described by the following examples, which are illustrative of specific embodiments of the invention, and various uses thereof. These exemplifications, which illustrating certain specific aspects of the invention, do not portray the limitations or circumscribe the scope of the disclosed invention.

[0142] Unless otherwise indicated, the practice of the present invention employs conventional techniques of cell culture, molecular biology, microbiology, recombinant DNA manipulation, immunology science, which are within the skill of the art. Such techniques are explained fully in the literature. See, e.g. Cell Biology: a Laboratory Handbook: J. Cells (Ed). Academic Press. N.Y. (1996); Graham, F. L. and Prevec, L. Adenovirus-based expression vectors and recombinant vaccines. In: Vaccines: New Approaches to Immunological Problems. R. W. Ellis (ed) Butterworth. Pp 363-390; Grahan and Prevec Manipulation of adenovirus vectors. In: Methods in Molecular Biology, Vol. 7: Gene Transfer and Expression Techniques. E. J. Murray and J. M. Walker (eds) Humana Press Inc., Clifton, N.J. pp 109-128, 1991; Sambrook et al. (1989), Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press; Sambrook et al. (1989), and Ausubel et al. (1995), Short Protocols in Molecular Biology, John Wiley and Sons.

Example 1. Virology and Recombinant Nucleic Acids

[0143] Standard techniques are used for recombinant nucleic acid methods, polynucleotide synthesis, and microbial culture and transformation (e.g., electroporation, lipofection). Generally, enzymatic reactions and purification steps are performed according to the manufacturer's specifications. The techniques and procedures are generally performed according to conventional methods in the art and various general references (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd. edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.), which are provided throughout this document. The nomenclature used herein and the laboratory procedures in analytical chemistry, organic synthetic chemistry, and pharmaceutical formulation and delivery, and treatment of patients. Methods for the construction of adenoviral mutants are generally known in the art. See Bett, A. J. et al, PNAS 1994 vol: 91, pages 8802-8806, Mittal, S. K., Virus Res., 1993, vol: 28, pages 67-90; and Hermiston, T. et al., Methods in Molecular Medicine: Adenovirus Methods and Protocols, W. S. M. Wold, ed, Humana Press, 1999. Further, the adenovirus 5 genome is registered as GenBank 10 accession #M73260, and the virus is available from the American Type Culture Collection, Rockville, Md., U.S.A., under accession number VR-5.

Viruses and Cell Lines

[0144] Adenoviruses and cell lines were generally obtained from American Type Culture Collection (ATCC), Manassas, Va.) unless otherwise noted. Cell lines used in the Examples below may include one or more of the cell lines listed in Table 2.

TABLE-US-00002 TABLE 2 Viruses and Cell Lines Cell Line Cell/Tissue Type Catalog # HEK-293 Normal human embryonic kidney ATCC .RTM. CRL-1573 .TM. MRC-5 Normal human lung ATCC .RTM. CCL-171 .TM. HMEC-1 Normal human endothelium ATCC .RTM. CRL3243 .TM. MCF 10A Normal human mammary epithelial ATCC .RTM. CRL-10317 .TM. NHLF Normal human lung fibroblasts Lonza CC-2512 HUVEC Normal human umbilical endothelium ATCC .RTM. CRL-1730 .TM. HCC827 lung adenocarcinoma ATCC .RTM. CRL-2868 .TM. A549 human lung carcinoma ATCC .RTM. CCL-185 .TM. ADS-12 a derivative from a murine KRAS mutant lung adenocarcinoma cell line (LKR-13) NCI-H1734 NSCLC adenocarcinoma ATCC .RTM. CRL-5891 .TM. NCI-H2110 NSCLC metastatic carcinoma ATCC .RTM. CRL-5924 .TM. HT-1080 Connective tissue fibrosarcoma ATCC .RTM. CCL121 .TM. PC-3 Prostate adenocarcinoma ATCC .RTM. CRL-1435 .TM. , SNU-449 Hepatocellular carcinoma ATCC .RTM. CRL-2234 .TM. HepG2 Hepatocellular carcinoma ATCC .RTM. HB-8065 .TM. MDA-MB-231 Breast adenocarcinoma ATCC .RTM. HTB-26 .TM. PANC-1 Pancreatic carcinoma ATCC .RTM. CRL-1469 .TM. SW780 Bladder carcinoma ATCC .RTM. CRL-2169 .TM. FaDu Head and neck squamous cell carcinoma ATCC .RTM. HTB43 .TM. DLD-1 Colorectal adenocarcinoma ATCC .RTM. CCL-221 .TM. CT26 Murine colon carcinoma ATCC .RTM. CRL-2638 .TM. U-87 brain glioblastoma ATCC .RTM. HTB14 .TM. MBT-2 Murine bladder cancer described, e.g., in Takahashi et al., J Urol, 166(6), 2506-2511 B16F10 Murine skin melanoma ATCC .RTM. CRL-6475 .TM. TAV-255 D19 Adenovirus described in, e.g., Zhang et al., Cancer Gene Ther. (2015) 22(1):17-22. Ad5 Adenoid 75 strain ATCC .RTM. VR-5 .TM.

Viral Purification and Quantitation

[0145] Viral stocks were propagated on HEK-293 cells and purified by standard methods such as column purification kits (Virapure, Millipore) or CsCl gradient centrifugation (as described in Tollefson, A., Hermiston, T. W., and Wold, W. S. M.; "Preparation and Titration of CsCl-banded Adenovirus Stock" in Adenovirus Methods and Protocols, Humana Press, 1999, pp 1-10, W. S. M. Wold, Ed.). The method used to quantitate viral particles is based on simple OD 260/280 readings, e.g., using the method of Lehmberg et al. (1999) J. Chrom. B, 732:411-423. In the viral concentration range used, the A260 nm peak area of each sample is directly proportional to the number of viral particles in the sample. The number of viral particles per ml in each test sample was calculated by multiplying the known number of viral particles per ml in the standard by the ratio of the A260 nm viral peak area of the sample to the A260 nm viral peak area of the standard. One A260 unit contains approximately 1.times.10.sup.12 viral particles. Virus Infectious Units/ml (IU/ml) were determined by hexon staining of infected cells (e.g., using Adeno-X.TM. Rapid titer kit from Takara Bio USA, Inc. (TBUSA, formerly known as Clontech Laboratories, Inc.).

Example 2. Bioselection

[0146] Initial screening of recombinant virus was based on isolated viral DNA rescued from transfected 293 cells where viral propagation based cytopathic effects (CPE) were observed. Viral DNA was used as a template for PCR based detection of sequences flanking the site of the TAV-255 E1a enhancer deletion region. Wild-type sequence would produce a band of 350 bp, while DNA which had the E1a enhancer deletion would only generate a clearly distinguishable 300 bp band. In addition, primers specific for internal sequences of the IL-12 transgene and for Ad hexon sequences were used to verify 400 bp and 3 kb PCR amplified bands respectively that would only be present in viral DNA generated by recombination between the two parental plasmids containing either the E1 region and transgene insert or the late Ad structural proteins derived solely from the pAdEasy.TM. plasmid. Individual constructs were isolated by two rounds of plaque purification on A549 or 293 cells using standard methods (Tollefson, A., Hermiston, T. W., and Wold, W. S. M.; "Preparation and Titration of CsCl-banded Adenovirus Stock" in Adenovirus Methods and Protocols, Humana Press, 1999, pp 1-10, W. S. M. Wold, Ed). Dilutions of adenoviral lysates were used to infect A549 or 293 cells in a standard plaque assay. Well-individuated plaques were harvested, and the same plaque assay method was used to generate a second round of individual plaques from these harvests. Well isolated plaques from the second round of plaque purification were deemed pure, infected cultures are prepared using these purified plaques, and the oncolytic potency and selectivity of these culture supernatants was determined.

Example 3. Cytolytic Assay

[0147] Tumor specific viral lysis was evaluated in both tumor and non-tumor cell lines of murine and human origin by infection of the cells in vitro with the viruses, followed by standard crystal violet for cell viability over time as instructed in the kit manuals.

Example 4. DNA Sequencing

[0148] DNA sequencing of the human Ad5-based recombinant adenovirus genomic DNAs was performed as follows. Viral DNA was purified from recombinant adenoviruses such as TAV-255 or other modifications of these constructs by standard column purification methods such as the Qia-amp.RTM. blood DNA purification kit from Qiagen.RTM.. PCR primers were used to amplify and isolate regions covering the E1a modified regions and the regions containing the transgene insert and sent out for sequencing at a CRO. Isolated DNA was also analyzed by standard restriction digestion and SDS PAGE analysis for verification of appropriate sized bands of digested DNA. Sequence information was analyzed using the Vector NTI program (Informatix).

Example 5. Construction of Recombinant Viruses

[0149] The base shuttle transfer vector includes pXC1 TAV 255 d19k (Zhang et al., Cancer Gene Ther. (2015) 22(1):17-22). This plasmid has a deletion between bp -305 to -255 of the E1a enhancer region, removing two Pea3 and one E2F binding sites which restrict replication and oncolysis of an adenovirus with this deletion to infected tumor cells (Hedrun, F. H., Shantanu K., and Reid, T. (2011) Cancer Gene Therapy 18; 717-723.) It also contains sites allowing deletion of the E1b 19k region and exogenous transgene insert by a Sal I/Xho I digest. Without the digest, the majority of the E1b 19k region is intact, but non-functional. cDNAs for each transgene of interest were synthesized (GeneArt.TM.) or isolated from commercial plasmid sources (GE Lifesciences or GeneCopoeia.TM.) by PCR using primers which added on 5' SalI and 3' XhoI restriction sequences for insertion into the SalI/XhoI digested pXC1 TAV 255 plasmids. The modified pXC1 TAV 255 gene insert plasmids were amplified in E. coli and purified using Qiagen.RTM. Maxi-prep plasmid kits.

[0150] To obtain recombinant adenoviruses, the pXC1 TAV 255 gene insert-containing plasmids were co-transfected into HEK-293 cells (ATCC) with pBHG10 (Microbix) as described (Bett, A. J., Haddara, W., Prevec, L., and Graham, F. (1994) PNAS 91; 8802-8806), using the calcium phosphate transfection protocol from Molecular Cloning: A laboratory manual (Maniatis Vol. 3; 16.30-16.36) for 2-5 .mu.g plasmid DNA (for both plasmids so the pXC1 will be in molar excess) per 60 mm dish of cells. Recombination between homologous adenovirus sequences from each plasmid generates a full length, replication competent adenovirus containing the E1 modifications described earlier and a specific transgene inserted into the E1b 19k deletion site and the E3 deletion supplied by the pBHG10 plasmid. Optionally, the pBHG10 is provided as the adenoviral genome source, having substantial additional utility over vectors such as pJM17 (See, e.g., Hedrun et al, (2011)). Preferentially, an E3 deletion and/or other modifications allow increased packaging capacity for exogenous genes in excess of pJM17 capacity.

[0151] In another embodiment, the human IL-12 virus, TRZ627, was constructed using a modification of the pAdEasy.TM. Adenoviral Vector System (Agilent Technologies). First, sequences from pXCI-TAV d19K plasmid (Hedjran F et al., Cancer Gene Therapy (2011) 18, 717-723) which included the 50-nucleotide deletion in the enhancer of E1A which restricts viral propagation to tumor vs. non-tumor cells, were subcloned into the pShuttle.TM. vector supplied in the pAdEasy.TM. kit to create the TAV-255 Shuttle E1 cloning plasmid. Sequences between the first Pac I site (6) and the single Mfe I site (807) in pShuttle were replaced by pXC1 TAV d19K sequences from the beginning of the 5' ITR sequence (21) to the Mfe I site (3874), corresponding to the same Mfe I site in pShuttle. A Pac I cloning site was added by PCR onto the 5' end of this fragment, which brought in Ad E1a and E1b sequence not found in the original pShuttle plasmid. The TAV-255 deletion of 50 bp in the E1a enhancer region removes the Pea3 III, Pea3 II, and an E2F transcription factor binding sites and corresponds to human wild-type Ad5 sequence of bases 194-244. The added sequences also included a modification introducing Sal I/Xho I cloning sites into the E1b 19k coding region which can be used to replace the E1b 19k ORF with an exogenous transgene insert whose expression would be driven by the Ad E1b promoter during viral replication. Recombination between Pme I linearized pTAV-255 Shuttle E1 containing hIL-12 cloned in at the E1b 19k site and the pAdEasy vector took place in the recA proficient BJ5183 bacterial strain, which had been modified to already contain the pAdEasy plasmid. DNA isolated from Kanamycin resistant plated colonies was screened for full-length viral DNA recombinants by restriction digest. Positive clones (TRZ-627, hIL-12) were subsequently digested with Pac I to free up the Ad ITRs and then transfected into 293 cells to amplify the virus.

[0152] Infected HEK-293 cells were collected when visible sign of cytopathic effects due to viral replication were observed up to 2 weeks post-infection and resuspended in their media and lysed by 3 rounds of freeze/thaw. Virus can be purified from the lysate by several methods, including Anion-exchange HPLC (Shabram, P. W., et al (1997) Human Gene Therapy 8; 453-465) or several commercially available kits based on affinity chromatography or size exclusion membranes or columns (e.g., Adeno-X.TM. Maxi Purification Kit, Clontech.RTM. (Takara), Adenovirus Purification Virakit.RTM., Virapur.RTM.). Purified virus can also undergo clonal isolation by standard plaque purification methods, followed by re-amplification and purification of the plaque purified viral clone.

Example 6. In Vivo Demonstration of Reduction in Tumor Volume with Oncolytic Adenoviral Vectors Encoding Immunomodulatory Polypeptides: Single Viruses with and without Antibody Treatment

Materials and Methods

[0153] An anti-mPD-L1 antibody is, e.g., from BioXCell.RTM., Catalog #BE0101 (Rat IgG2b). This antibody was used in the below experiments.

[0154] Virus samples were stored in 25 mM NaCl, 10 mM Tris Tris(hydroxymethyl)aminomethane), and 5% glycerol with a pH value of 8.0. Vials were stored protected from light at -80.degree. C. On each day of dosing, one vial was thawed at room temperature for approximately 20 minutes. A single dose is 1.times.10.sup.9 pfu.

[0155] The mouse tumor model in this Example uses syngeneic immunocompetent mice. Female Jackson 129S1 (129S1/Sv1mJ) mice were used in this study. They were 6-7 weeks old on Day 1 of the experiment. The animals were fed irradiated Harlan 2918.15 Rodent Diet and water ad libitum. Animals were housed in static cages with Bed-O'Cobs.RTM. bedding inside bioBubble.RTM. Clean Rooms that provide H.E.P.A filtered air into the bubble environment at 100 complete air changes per hour. All treatments, body weight determinations, and tumor measurements were carried out in the bubble environment. The environment was controlled to a temperature range of 70.degree..+-.2.degree. F. and a humidity range of 30-70%.

Cell Preparation

[0156] ADS-12 cells were grown in RPMI 1640 medium which was modified with 1% 100 mM Na pyruvate, 1% 200 mM L-glutamine, 1% 1M HEPES buffer, 1% of a 45% glucose solution and supplemented with 10% non-heat-inactivated Fetal Bovine Serum (FBS) and 1% 100.times. Penicillin/Streptomycin/L-Glutamine (PSG). The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C. When expansion was complete, the cells (passage 7) were trypsinized using 0.25% trypsin/2.21 mM EDTA in HBSS solution. Following cell detachment, the trypsin was inactivated by dilution with complete growth medium and any clumps of cells were separated by pipetting. The cells were centrifuged at 200 rcf for 8 minutes at 4.degree. C., the supernatant was aspirated, and the pellet was re-suspended in cold Dulbecco's Phosphate Buffered Saline (DPBS) by pipetting. An aliquot of the homogeneous cell suspension was diluted in a trypan blue solution and counted using a Luna automated cell counter. The cell suspension was centrifuged at 200 rcf for 8 minutes at 4.degree. C. The supernatant was aspirated and the cell pellet was re-suspended in cold Dulbecco's Phosphate Buffered Saline (DPBS) to generate a final concentration of 1.times.10.sup.7 trypan-excluding cells/ml. The cell suspension was maintained on wet ice during implantation. Following implantation, an aliquot of the remaining cells was diluted with a trypan blue solution and counted to determine the post-implantation cell viability. The cell viabilities of the suspensions used for implantation (two preps) are listed in Table 3.

TABLE-US-00003 TABLE 3 Implantation Cell Viability Pre-Implant Viability (%) Post-Implant Viability (%) Cell Prep 1 95 89 Cell Prep 2 95 89

[0157] Test animals were implanted subcutaneously on both flanks (on the back between the spine and the hip), the right flank on Day 0 and the left flank on Day 8, with 1.times.10.sup.6 cells in 0.1 ml of serum-free medium using a 28-gauge insulin syringe with a fixed needle.

[0158] All mice were sorted into study groups based on caliper measurement estimation of tumor burden on Day 15 when the mean tumor burden for all animals on the right flank was approximately 82 mm.sup.3 (range of group means, 75-90 mm.sup.3). The mice were distributed to ensure that the mean tumor burden on the right flank for all groups was within 10% of the overall mean tumor burden for the study population.

Results

[0159] The mean estimated right side tumor burden for all groups in the experiment on the first day of treatment was 82 mm3 and all of the groups in the experiment were well-matched (range of group means, 75-90 mm3). All animals weighed at least 13.3 g at the initiation of therapy. Mean group body weights at first treatment were also well-matched (range, 15.4-18.3 g). A tumor burden of 500 mm3 was chosen for evaluation of efficacy by tumor growth delay for the right and left tumors. The median Control Group (FIG. 6A) tumor burdens reached 500 mm3 on Day 47 for right tumors and Day 43 for left tumors. The median tumor volume doubling times for the Control Group were 12.1 and 10.1 days for the right and left tumors, respectively. Control animals experienced a 7.3% mean weight gain during the treatment regimen. There were no spontaneous regressions in the Control Group for either right or left side tumors, however, 50% of the tumors on the left side never reached the palpation limit. In some embodiments, mice with palpable left side tumors were put on study. Since in this experiment the implant was delayed 8 days, the left side tumors were not palpable at staging. These mice that had a left side tumor that remained a 0 throughout the study could have been triaged out of the study if implanted on the same day as the right side.

[0160] Results of mouse inoculation and tumor growth are shown in FIG. 6A, FIG. 6B, FIG. 6C, FIG. 6D, FIG. 6E, FIG. 6F, FIG. 6G, FIG. 6H, FIG. 6I, FIG. 6J, FIG. 6K, and FIG. 6L. The series of graphs shows treatment of tumor bearing mice (n=8 in each group) with oncolytic viruses comprising various transgenes, with or without anti-PD-L1.

[0161] FIG. 6A is a graph showing the activity of various oncolytic viruses compared to the empty virus ("d19k"), 38 days after cell implantation (primary tumor) as a function of tumor growth inhibition. Black bars represent virus alone and hatched bars represent virus+anti-PD-L1 antibody. FIG. 6B is a graph comparing the average tumor size (primary tumor) over time of tumors injected with virus buffer (black circles), empty vector (blue solid squares), anti-PD-L1 alone (antibody given on days 16, 20, 24, and 28, right-hand arrow in each pair of arrows), each of five viruses alone (viruses carrying CTLA-4, IL-12, IL-7, CD70, and IL-10 transgenes) or combined with anti-PD-L1 antibody. FIG. 6C shows similar data for three more viruses (viruses carrying OX40L, CD40L, and GM-CSF transgenes). As shown in FIG. 6A, FIG. 6B, and FIG. 6C, the IL-12 oncolytic virus treatment, alone or in combination with an anti-PD-L1 antibody, were the most effective at reducing tumor growth. CD70, IL-7, and CTLA-4 viruses were also able to reduce tumor volume significantly when combined with the anti-PD-L1 antibody.

[0162] The following Figures (FIG. 6D, FIG. 6E, FIG. 6F, FIG. 6G, FIG. 6H, FIG. 6I, FIG. 6J, FIG. 6K, and FIG. 6L) demonstrate efficacy (or lack thereof) of various viruses with transgenes with or without PD-L1 on the primary tumor only; the thick line in each graph shows the average tumor volume in mm.sup.3. The pairs of arrows on the x-axis represent day of treatment with virus (intratumoral, left arrows) and the anti-PD-L1 antibody, if used (intraperitoneal, right arrows). Treatments are shown for the primary tumor (receiving the oncolytic virus injection) and are as follows: FIG. 6D, virus buffer and control IgG only (left) and virus buffer and anti-PD-L1 antibody (right); FIG. 6E, d19k (empty virus) and control IgG only (left) and d19k and anti-PD-L1 antibody (right); FIG. 6F, CTLA-4 virus with control IgG (left) or anti-PD-L1 (right); FIG. 6G, IL-12 virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6H, GM-CSF virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6I, IL-7 virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6J, CD40L virus with control IgG (left) or anti-PD-L1 antibody (right); FIG. 6K, L10 trap virus with control IgG (left) or anti-PD-L1 antibody (right); and FIG. 6L, OX40L virus with control IgG (left) or anti-PD-L1 antibody.

[0163] As shown in FIG. 6G, FIG. 6I, FIG. 6F and FIG. 6J, combinations with the IL-12 adenovirus (FIG. 6G), showed the greatest ability to reduce tumor volume. As in FIG. 6A, the IL-7 (FIG. 6I) and CTLA-4 (FIG. 6F) oncolytic viruses also showed activity when combined with anti-PD-L1 antibody. Treatment with the oncolytic virus encoding the CD40 ligand also showed some activity when combined with the anti-PD-L1 antibody (FIG. 6J).

Example 7. In Vivo Demonstration of Reduction in Tumor Volume with Oncolytic Adenoviral Vectors Encoding Immunomodulatory Polypeptides: Virus Mixing Study

[0164] The mouse tumor model in this Example uses syngeneic immunocompetent mice. Animals were injected with approximately 1,000,000 cells subcutaneously (s.c.) into the right hind flank of the mouse. At the same time, the mice were also injected with 1,000,000 cells s.c. into the left hind flank of the mouse to create a bilateral tumor model. When the right (primary) tumors reached 63-80 mm.sup.3 in size and the left tumor was palpable, they were injected with 25 .mu.l of virus buffer or 25 .mu.l of virus at 4.times.10.sup.9 pfu/ml (plaque forming units per ml) directly into the center of the primary tumor every fourth day for a total of three doses. The mice were also treated intraperitoneally with 250 .mu.l of an anti-PD-L1 antibody at 2 mg/ml every fourth day for a total of three doses. The antibody was administered 24 hours after administration of the virus. A reduction in the size of the primary and distal (contralateral) tumor would be noted relative to the virus buffer control and additional controls such as the wild-type virus (not expressing a transgene) with or without administration of the anti-PD-L1 antibody. A specific example of the treatment with oncolytic adenoviral vectors is described in more detail below for a panel of such vectors.

[0165] Evaluation of the primary tumor (right flank) was used to determine the direct effect of the oncolytic viruses whereas evaluation of the contralateral tumor (left flank) was used to see the systemic effects of the oncolytic viruses. ADS-12 (a murine KRAS-mutant lung adenocarcinoma cell line) grown in its syngeneic mouse strain is a tumor model known to support adenoviral infection and replication and is useful in the evaluation of host immune responses to oncolytic human adenoviruses.

Materials and Methods

[0166] An anti-mPD-L1 antibody is, e.g., from BioXCell.RTM., Catalog #BE0101 (Rat IgG2b). This antibody was used in the below experiments.

[0167] Virus samples were stored in 25 mM NaCl, 10 mM Tris Tris(hydroxymethyl)aminomethane), and 5% glycerol with a pH value of 8.0. Vials were stored protected from light at -80.degree. C. On each day of dosing, one vial was thawed at room temperature for approximately 20 minutes.

Animal Studies

[0168] Female 129S1 (129S1/SvImJ) mice from The Jackson Laboratory were used in this study. They were approximately 7-8 weeks old on Day 14 of the experiment. The animals were fed irradiated Harlan 2918.15 Rodent Diet and water ad libitum. Animals were housed in static cages with Bed-O'Cobs.RTM. bedding inside BioBubble.RTM. Clean Rooms that provide H.E.P.A filtered air into the bubble environment at 100 complete air changes per hour. All treatments, body weight determinations, and tumor measurements were carried out in the bubble environment. The environment was controlled to a temperature range of 70.degree..+-.2.degree. F. and a humidity range of 30-70%. All procedures carried out in this experiment were conducted in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH) and with the approval of Molecular Imaging, Inc.'s Animal Care and Use Committee. Molecular Imaging, Inc. is an AAALAC accredited facility.

Cell Preparation

[0169] ADS-12 cells (murine KRAS-mutant lung adenocarcinoma) were grown in RPMI 1640 medium which is modified with 1% 100 mM Na pyruvate, 1% 200 mM L-glutamine, 1% 1M HEPES buffer, 1% of a 45% glucose solution and supplemented with 10% non-heat-inactivated Fetal Bovine Serum (FBS) and 1% 100.times. Penicillin/Streptomycin/L-Glutamine (PSG). The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C. When expansion as complete, the cells are trypsinized using 0.25% trypsin/2.21 mM EDTA in HBSS solution. Following the cell viabilities of the suspensions used for implantation (two preps) are listed in the table below.

TABLE-US-00004 TABLE 4 Implantation Cell Viability Pre-Implant Viability (%) Post-Implant Viability (%) Cell Prep 1 94 92 Cell Prep 2 97 92

[0170] Test animals were implanted subcutaneously, on both flanks (on the back between the spine and the hip) on Day 0 with 1.00.times.10.sup.6 cells in 0.1 ml of serum-free medium using a 28-gauge insulin syringe with a fixed needle.

Treatment

[0171] All mice were sorted into study groups based on caliper measurement estimation of tumor burden on Day 14 when the mean tumor burden for all animals on the right flank is approximately 68 mm.sup.3 (range of group means, 65-71 mm.sup.3). The mice were distributed to ensure that the mean tumor burden for all groups was within 10% of the overall mean tumor burden for the study population.

Measurement and Endpoints

[0172] Tumor burden (mm.sup.3) was estimated from caliper measurements by the formula for the volume of a prolate ellipsoid assuming unit density as: Tumor burden (mm.sup.3)=(L.times.W.sup.2)/2, where L and W are the respective orthogonal tumor length and width measurements (mm). All groups were compared to the virus buffer control group.

[0173] The primary endpoints used to evaluate efficacy were: tumor growth delay, complete and partial tumor response, and the number of tumor-free survivors at the end of the study for both left and right tumors. A complete response (CR) is defined as a decrease in tumor mass to an undetectable size (<63 mm.sup.3), and a partial response (PR) is defined as a smaller tumor mass at the last measurement compared to at the first treatment. PRs are exclusive of CRs.

[0174] All animals were observed for clinical signs at least once daily. Animals were weighed on each day of treatment. Individual body weights were recorded three times weekly. Animals with combined tumor burdens in excess of 2000 mm.sup.3 were euthanized, as were those found in obvious distress or in a moribund condition. Treatment-related weight loss in excess of 20% is generally considered unacceptably toxic. In this Example, a dosage level was determined to be tolerated if treatment-related weight loss (during and two weeks after treatment) was <20% and mortality during this period in the absence of potentially lethal tumor burdens was .ltoreq.10%.

Results

[0175] Results of mouse inoculation and tumor growth are shown in FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, FIG. 7F, FIG. 7G, FIG. 7H, FIG. 7I, FIG. 7J, FIG. 7K, FIG. 7L, FIG. 7M, FIG. 7N, FIG. 7O, FIG. 7P, FIG. 7Q, FIG. 7R, FIG. 7S, FIG. 7T, FIG. 7U, FIG. 7V, FIG. 7W, FIG. 7X, FIG. 7Y, FIG. 7Z, and FIG. 7AA. The series of graphs shows treatment of tumor bearing mice (n=8 in each group) with single and combinations of oncolytic viruses comprising various transgenes, with or without anti-PD-L1. The left-hand panel of each Figure represents the primary tumor into which the virus was injected; the right-hand panel represents the contralateral tumor. The thick line in each graph shows the average tumor volume in mm.sup.3. The pairs of arrows on the x-axis represent day of treatment with virus (intratumoral, left arrows) and the anti-PD-L1 antibody, if used (intraperitoneal, right arrows). A summary of the responses of the 8 mice is shown in a table at the bottom of each graph, wherein CR=Complete Response (tumor volume=0) and PR=Partial Response (tumor volume on last day of measurements is smaller than tumor volume on the first day of measurements). Treatments shown are as follows: FIG. 7A, virus buffer only; FIG. 7B, empty virus only (TRZ000); FIG. 7C, TRZ010 (IL-10trap)+empty virus; FIG. 7D, TRZ011 (OX40 ligand)+empty virus; FIG. 7E, TRZ009 (CD70)+empty virus; FIG. 7F, TRZ007 (IL-7)+empty virus, FIG. 7G, TRZ002 (IL-12)+empty virus; FIG. 7H, TRZ004 (GM-CSF)+empty virus; FIG. 7I, TRZ003 (flagellin)+empty virus; FIG. 7J, TRZ002+TRZ010; FIG. 7K, TRZ002+TRZ007; FIG. 7L, TRZ007+TRZ010; FIG. 7M, TRZ011+TRZ004; FIG. 7N, TRZ009+TRZ003; FIG. 7O, TRZ002+TRZ009; FIG. 7P, TRZ007+TRZ009; FIG. 7Q, TRZ007+TRZ004; FIG. 7R, TRZ002+TRZ011; FIG. 7S, TRZ010+TRZ004; FIG. 7T, TRZ002+TRZ004; FIG. 7U, virus buffer and anti-PD-L1; FIG. 7V, TRZ002+empty virus+anti-PD-L1; FIG. 7W, TRZ009+anti-PD-L1; FIG. 7X, TRZ007+empty virus+anti-PD-L1; FIG. 7Y, TRZ002+TRZ007+anti-PD-L1; FIG. 7Z, TRZ007+TRZ009+anti-PD-L1; and FIG. 7AA, TRZ002+TRZ009+anti-PD-L1. All viruses were administered at 1.times.10.sup.8pfu/dose for each virus, resulting in 2.times.10.sup.8 pfu total in virus combinations.

[0176] As can be seen in FIG. 7G, FIG. 7K, FIG. 7V and FIG. 7AA, certain combinations of virus transgenes were extremely successful in lysing tumor cells, including a number of examples of complete response. For example, FIG. 7G shows tumor volume in mice treated with an IL-12 adenovirus. 5 out of 8 mice in FIG. 7G had a complete response, and one mouse had a partial response. In the contralateral tumor, however, no complete or partial responses were seen, indicating that there were no systemic immune effects from treatment with the IL-12 virus alone. A better result is seen in FIG. 7K, which shows mice treated with the same IL-12 adenovirus in combination with an IL-7 adenovirus. In this group of mice, 7 out of 8 had a complete response in the primary tumor (into which the virus was injected) and in the contralateral tumor two mice showed a complete response and one a partial response. In FIG. 7V (IL-12 adenovirus+anti-PD-L1 antibody) and FIG. 7AA (IL-12 adenovirus+CD70 adenovirus+anti-PD-L1 antibody), each group of 8 mice had 8 complete responses in the primary tumor and several in the contralateral tumor. These data demonstrate that certain combination therapies comprising oncolytic adenoviruses can be useful in treating primary and metastatic tumors.

Example 8. Adenoviral Vectors Expressing Multiple Immunomodulatory Polypeptides

[0177] If deletions in the adenovirus backbone are sufficiently large enough to allow packaging of viral DNA containing two exogenously added transgenes into the viral capsids, the two genes can be co-expressed by several methods from a single deletion site in adenovirus. Both added genes can be linked to each other by methods described below and have their expression controlled by an endogenous adenovirus promoter, not an exogenously added promoter, so that high expression will only occur during conditions of viral replication. Control of restricting viral replication to certain conditions such as after infection of tumor cells, is described elsewhere in this document. Co-expression of two proteins from a single transcript can be achieved through the use of virus components such as internal ribosome entry site (IRES) elements (Renaud-Gabardos E et al, World J Exp Med 2015, 5: 11-20), insertion of self-cleaving 2A peptide sequences derived from viruses such as Foot and Mouth Disease virus (FMDV) (Garry A. Luke (2012), Translating 2A Research into Practice, Innovations in Biotechnology, Dr. Eddy C. Agbo (Ed.), ISBN: 978-953-51-0096-6, InTech), or by combining the sequences of the two transgenes into a single fusion protein. An exemplary method would use one of the 2A sequences to direct more equal level of expression from both transgenes as opposed to lower expression levels typically seen from the second transgene when using IRES elements.

[0178] To maintain co-expression from two single gene inserts at different sites, the cDNA for each transgene can be inserted into separate deleted regions of adenovirus so that expression of each would be controlled separately by the endogenous upstream adenovirus promoter. No exogenous promoter would be added with the exogenous transgene sequence. Expression of the E1a proteins leads to the activation of the other adenovirus promoters and viral replication, so expression from each endogenous adenovirus promoter is linked to viral replication. Exogenous transgenes inserted behind different adenovirus promoters, such as the E1b promoter, the E3 promoter, and the E4 promoter, in place of deletions in these regions, leads to a construct where co-expression from each inserted transgene is limited to conditions of where viral replication occurs. Combined with modifications in the E1a enhancer region as described previously in this document to restrict viral replication to tumor cells, co-expression of both exogenous transgenes is restricted to tumor cells.

[0179] As shown schematically in FIG. 2, provided is an .DELTA.E1b19K site that includes a deletion of bp 1714-1916 (numbered according to hAd5 vector sequence), which increases packaging capacity by approximately 200 bp. Also provided is a deletion at the E3 site (.DELTA.E3 site as shown in FIG. 2); this deletion can be any deletion in the E3 region, generally at or about bp 27,900-30,800 bp (numbered according to hAd5 vector sequence), which increases packaging capacity up to an additional approximately 2400 bp, as compared to most wild type adenoviruses, which are typically limited to containing (i.e., packaging) approximately 1800 bp of exogenous sequences.

[0180] Provided herein are deletions in E3 open reading frames that are suitable for modification (e.g., truncation or deletion) without substantially decreasing viral propagation. By way of non-limiting example, provided are adenoviral vectors wherein the E3 12.5K coding region (27,852-28,175 bp) is truncated (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 320 or greater than 320 bases are deleted from one or more truncation sites within the region) or entirely deleted. Also provided are adenoviral vectors wherein the E3 7.1K coding region (28,541-28,732) is truncated (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or greater than 190 bases are deleted from one or more truncation sites within the region) or entirely deleted. The 7.1K sequence is associated with inhibition of TRAIL apoptosis and associated with one or more RID proteins. Also provided are adenoviral vectors wherein the E3 gp19K (28,729-29211) is truncated (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450 or greater than 450 bases are deleted from one or more truncation sites within the region) or entirely deleted. The gp19K sequence is associated with inhibition of CTL killing. Also provided are adenoviral vectors wherein the E3 10.5 (also called E3 11.6 (ADP)) (29,485-29,766) is truncated (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, or greater than 250 bases are deleted from one or more truncation sites within the region) or entirely deleted. The 10.5 sequence is associated with promotion of virus release. Also provided are adenoviral vectors wherein the E3 (RID.alpha.) (29,778-29,969) and/or the E3 (RID.beta.) (30,057-30,455) is truncated (e.g., with respect to E3 (RID.alpha.) at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or greater than 190 bases are deleted from one or more truncation sites within the region) or entirely deleted, or truncated (e.g., with respect to E3 (RID.beta.) at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 390, or greater than 390 bases are deleted from one or more truncation sites within the region) or entirely deleted. These RID sequences are associated with inhibition of TNF, FasL, and TRAIL apoptosis and degrade EGFR. Any combination of the above-referenced deletions is also provided.

[0181] Also provided are adenoviral vectors wherein the E3 14.7K (30,488-30,834) is truncated (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 340, or greater than 340 bases are deleted from one or more truncation sites within the region) or entirely deleted. The 14.7K sequence is associated with inhibition of TNF, FasL, and TRAIL apoptosis.

[0182] Descriptions of exemplary dual transgene constructs shown in Table 5 in this Example and Table 6 in Example 13. As can be seen in the table, any of the transgenes may be inserted into the E1 or E3 region. For example, in one embodiment a dual transgene construct may have IL-12 inserted into the E1 region and IL-2 in the E3 region. In another embodiment, a dual transgene construct may have IL-2 inserted into the E1 region and IL-12 in the E3 region. Use of the dual transgene constructs in therapeutic oncolytic adenoviruses is described in Examples 9 and 13.

TABLE-US-00005 TABLE 5 Exemplary dual transgene constructs. TRZ Number Brief Description TRZ402* TAV-255-d19kE1-mIL-10T-E3-mIL-12 TRZ403* TAV-255-d19kE1-mIL-7-E3-mIL-12 TRZ404* TAV-255-d19kE1-mCD70-E3-IL-12 TRZ405 TAV-255-d19kE1-mOX40L-E3-mGM-CSF TRZ406 TAV-255-d19kE1-mIL-10T-E3-mIL-7 TRZ407 TAV-255-d19kE1-mIL-12-E3-mIL-10T TRZ408 TAV-255-d19k-E3-mIL-12 TRZ409 E1-mIL-12/E3-mIL-7 TRZ413 E1-mIL-7/E3-mIL-12-P2A-ADP TRZ418* E1-trimeric mCD70/E3-mIL-12 TRZ421* E1-mIL-2/E3-mIL-12 TRZ501 TAV-255-d19K Dual mIL-10T-P2A-mIL-12, E3 deleted TRZ510 E1-mIL-7-P2A-mIL-12 TRZ512 E1-mIL-12-P2A-mIL-7 m = murine; P2A = cleavage site *See also Table 6

Example 9. Adenoviral Vectors Expressing an Immunomodulatory Polypeptide from the E4 Region

[0183] A nucleic acid sequence encoding one or more immunomodulatory polypeptides is inserted into the adenoviral genome by truncation or deletion of a portion of the E4 region of the viral genome. An E4 deletion and exogenous insertion can be utilized in combination with any other viral modification provided herein or otherwise known in the art, or alternatively, without any other viral modification. Exemplary E4 regions useful as insertion sites include truncation or deletion of E4 ORF1 (35,136-35,522 bp) and/or E4 ORF2 (34,696-35,106 bp) (each numbered according to hAd5 vector sequence). The expression of the one or more immunomodulatory polypeptides is controlled by the endogenous E4 promoter. A schematic illustration of this embodiment is provided in FIG. 3.

Example 10. Adenoviral Vectors Comprising Altered Configuration of Pea3 Sites

[0184] Adenoviral vectors are designed in which sequences in and around Pea3 sites I-V near the E1a Enhancer region of adenoviral vectors, in which sequences in and around Pea3 sites are altered, moved, or deleted in order to produce vectors with a variety of expression characteristics. In one embodiment, adenovirus vectors are engineered which have lower affinity Pea3 sites compared to wild-type adenoviral vectors. Such vectors are designed to be efficient in cells in the tumor microenvironment where the concentration of transcription factors is high, but to be relatively inactive in normal (e.g., non-neoplastic) cells, thus reducing the possibility of side effects caused by damage to normal tissue cells. An illustration of the E1a area of wild-type and TAV-255 constructs is shown in FIG. 9A. A cartoon illustration of the proposed method of action of the E1a enhancer region mutants is shown in FIG. 9B. Constructs NV1 to NV7 are based in part on the TAV-255 construct.

[0185] In one embodiment, a vector is provided wherein, (in relation to the wild-type sequence) the sequence is removed between Pea3 IV and Pea3 III sites, a single mutation is made in Pea3 III, the sequence between Pea3 III and Pea3 II, and the Pea3 II site is mutated. The sequence of the E1a enhancer region of the exemplary construct NV1 is set forth in SEQ ID NO:99.

[0186] In another embodiment, a vector is provided wherein, (in relation to the wild-type sequence) the sequence is removed between Pea3 IV and Pea3 III sites, both Pea3 III and Pea3 II are mutated, and Pea3 V flanking sites are mutated such that the resultant Pea3 V site has an affinity more similar to Pea3 III and enhancer 1. The sequence of the E1a enhancer region of the exemplary construct NV2 is set forth in SEQ ID NO:100.

[0187] In another embodiment, a vector is provided wherein, (in relation to the wild-type sequence) the sequence between Pea3 V and Pea3 IV sites is replaced with the sequence between the Pea3 III and Pea3 II sites; the sequence between the Pea3 IV and Pea3 III is deleted; the sequence between the Pea3 III and Pea3 II is deleted; and the Pea3 III and Pea3 II sites are both mutated, as well as the residues 3 bp that are immediately 5' of the Pea3 V site. The sequence of the E1a enhancer region of the exemplary construct NV3 is set forth in SEQ ID NO:101.

[0188] In another embodiment, a vector is provided wherein, (in relation to the wild-type sequence) the flanking sequences around the Pea3 III and Pea3 II sites are altered to mimic the lower affinity Pea3 V and Pea3 IV sites (thus engineering a vector in which all Pea3 sites except Pea3 I are lower affinity). The sequence of the E1a enhancer region of the exemplary construct NV4 is set forth in SEQ ID NO:102.

[0189] In another embodiment, a vector is provided wherein, (in relation to the wild-type sequence) the flanking sequences around the Pea3 III and Pea3 II sites are altered to mimic the lower affinity Pea3 V and Pea3 IV sites, and a single point mutation is introduced in the Pea3 I site, rendering it a lower affinity Pea3 I site (thus engineering a vector in which all Pea3 sites are lower affinity). The sequence of the E1a enhancer region of the exemplary construct NV5 is set forth in SEQ ID NO:103.

[0190] In another embodiment, a vector is provided wherein, (in relation to the wild-type sequence), the flanking sequences around the Pea3 III and Pea3 II sites are altered to mimic the lower affinity Pea3 V and Pea3 IV sites, and the flanking regions of the Pea3 I site are altered, rendering it a lower affinity Pea3 I site (thus engineering a vector in which all Pea3 sites are lower affinity). The sequence of the E1a enhancer region of the exemplary construct NV6 is set forth in SEQ ID NO:104.

[0191] In another embodiment, a vector is provided wherein, (in relation to the wild-type sequence) the flanking sequences around the Pea3 I site are altered to produce a lower-affinity Pea3 I site, and the flanking sequences around the Pea3 II site is altered to mimic the lower affinity Pea3 IV site (thus engineering a vector in which all Pea3 sites except Pea3 III are lower affinity). The sequence of the E1a enhancer region of the exemplary construct NV7 is set forth in SEQ ID NO:105.

Example 11. In Vivo Demonstration of Reduction in Tumor Volume with Oncolytic Adenoviral Vectors Comprising E1a Enhancer Region Alterations and Encoding Immunomodulatory Polypeptides: Single Viruses with and without Antibody Treatment

Materials and Methods

[0192] An anti-mPD-L1 antibody is, e.g., from BioXCell.RTM., Catalog #BE0101 (Rat IgG2b). This antibody was used in the below experiments.

[0193] Virus samples are stored in 25 mM NaCl, 10 mM Tris Tris(hydroxymethyl)aminomethane), and 5% glycerol with a pH value of 8.0. Vials are stored protected from light at -80.degree. C. On each day of dosing, one vial is thawed at room temperature for approximately 20 minutes. A single dose is 1.times.10.sup.9 pfu. Viruses to be combined with anti-PD-L1 in this Example include NV1-NV7 (having E1a enhancer region sequences set forth in SEQ ID Nos:99-105).

[0194] The mouse tumor model in this Example uses syngeneic immunocompetent mice. Female Jackson 12951 (12951/Sv1mJ) mice are used in this study. Mice are 6-7 weeks old on Day 1 of the experiment. The animals are fed irradiated Harlan 2918.15 Rodent Diet and water ad libitum. Animals are housed in static cages with Bed-O'Cobs.TM. bedding inside bioBubble.RTM. Clean Rooms that provide H.E.P.A filtered air into the bubble environment at 100 complete air changes per hour. All treatments, body weight determinations, and tumor measurements are carried out in the bubble environment. The environment is controlled to a temperature range of 70.degree..+-.2.degree. F. and a humidity range of 30-70%.

Cell Preparation

[0195] ADS-12 cells are grown in RPMI 1640 medium which is modified with 1% 100 mM Na pyruvate, 1% 200 mM L-glutamine, 1% 1M HEPES buffer, 1% of a 45% glucose solution and supplemented with 10% non-heat-inactivated Fetal Bovine Serum (FBS) and 1% 100.times. Penicillin/Streptomycin/L-Glutamine (PSG). The growth environment is maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C. When expansion is complete, the cells (passage 7) are trypsinized using 0.25% trypsin/2.21 mM EDTA in HBSS solution. Following cell detachment, the trypsin is inactivated by dilution with complete growth medium and any clumps of cells are separated by pipetting. The cells are centrifuged at 200 rcf for 8 minutes at 4.degree. C., the supernatant is aspirated, and the pellet is re-suspended in cold Dulbecco's Phosphate Buffered Saline (DPBS) by pipetting. An aliquot of the homogeneous cell suspension is diluted in a trypan blue solution and counted using a Luna automated cell counter. The cell suspension is centrifuged at 200 rcf for 8 minutes at 4.degree. C. The supernatant is aspirated and the cell pellet is re-suspended in cold Dulbecco's Phosphate Buffered Saline (DPBS) to generate a final concentration of 1.times.10.sup.7trypan-excluding cells/ml. The cell suspension is maintained on wet ice during implantation. Following implantation, an aliquot of the remaining cells is diluted with a trypan blue solution and counted to determine the post-implantation cell viability.

[0196] Test animals are implanted subcutaneously on both flanks (on the back between the spine and the hip), the right flank on Day 0 and the left flank on Day 8, with 1.times.10.sup.6 cells in 0.1 ml of serum-free medium using a 28-gauge insulin syringe with a fixed needle.

[0197] All mice are sorted into study groups based on caliper measurement estimation of tumor burden on Day 15 when the mean tumor burden for all animals on the right flank is approximately 82 mm.sup.3 (range of group means, 75-90 mm.sup.3). The mice are distributed to ensure that the mean tumor burden on the right flank for all groups is within 10% of the overall mean tumor burden for the study population.

Results

[0198] The mean estimated right side tumor burden for all groups in the experiment on the first day of treatment is approximately 82 mm.sup.3 and all of the groups in the experiment are well-matched (range of group means, 75-90 mm.sup.3). All animals weigh at least 13.3 g at the initiation of therapy. Mean group body weights at first treatment are also well-matched (range, approximately 15.4-18.3 g). A tumor burden of 500 mm.sup.3 is chosen for evaluation of efficacy by tumor growth delay for the right and left tumors. The median Control Group tumor burdens will reach 500 mm.sup.3 on or about Day 47 for right tumors and on or about Day 43 for left tumors. The median tumor volume doubling times for the Control Group will be approximately 12 and 10 days for the right and left tumors, respectively.

[0199] Results of mouse inoculation and tumor growth will show that treatment of tumor bearing mice with oncolytic viruses comprising altered E1a regions and encoding various transgenes, with or without anti-PD-L1, show efficacy in reducing tumor volume.

Example 12. In Vivo Efficacy of Dual-Specificity Oncolytic Adenoviral Vectors in a Bilateral Tumor Model

[0200] Cancer immunotherapy is moving toward use of combinations to increase efficacy. Combining cancer immunotherapies can expand clinical benefits of existing approved monotherapies; however, systemically-administered combinations can produce excessive toxicity. Therefore, novel dual specificity oncolytic adenoviral vectors were developed having a transgene at both the E1 and the E3 regions in order to evaluate combinations of adenoviral-delivered immunomodulators to enhance systemic antitumor immunity. A summary of exemplary constructs contemplated for use by the methods disclosed herein (with additions to those disclosed in Table 5) is listed in Table 6.

TABLE-US-00006 TABLE 6 Exemplary E1/E3 Dual Transgene Constructs and Single Transgene Comparators (*) Name E1 E3 TRZ-001* CTLA-4 Del TRZ-009* CD70 intact TRZ-018* CD70 trimer Del TRZ-021* Empty IL-2 TRZ-032* IL-2 Empty (has 12.5K protein) TRZ-401 CTLA4 IL-12 TRZ-402 IL-10 Trap IL-12 TRZ-403 IL-7 IL-12 (has 12.5K protein) TRZ-404 CD70 IL-12 TRZ-408* Empty IL-12 TRZ-409 IL-12 IL-7 TRZ-411 OX40L IL-12 TRZ-412 IL-2 IL-12 TRZ-414 CD40L IL-12 TRZ-415 IL-12 CTLA4 TRZ-416 OX40L (trimer) IL-12 TRZ-417 CD40L (trimer) IL-12 TRZ-418 CD70 (trimer) IL-12 TRZ-421 IL-12 IL-2 TRZ-510 IL-7-P2A-IL-12 TRZ-202-like (no 12.5) TRZ-TBD IL-7-P2A-IL-12 IL-2

[0201] A bilateral tumor model was prepared using ADS-12 tumor cells as described in the Examples above (e.g., Example 7). 1.times.10.sup.6 ADS-12 tumor cells injected into primary (-2 days) and contralateral (0 days) flanks. At staging, mice are randomized based on contralateral tumors (88-150 mm.sup.3) and primary tumors (88-250 mm.sup.3). There are 8 mice/group, with tumors and body weight measured 3 times per week. An anti-PD-L1 (500 .mu.g/dose) or an anti-PD-1 antibody (250 .mu.g/dose) is administered i.p. to induce systemic T cell activation.

[0202] In this model, the virus is injected intratumorally (it) into primary tumors only; such injection leads to oncolysis, immune infiltration, and tumor shrinkage. The contralateral tumor is not injected, and no oncolysis occurs. Rather, tumor shrinkage is solely due to antigen-specific activated tumor infiltrating lymphocytes.

[0203] Results are shown in FIG. 9A, FIG. 9B, FIG. 9C, FIG. 9D, FIG. 9E, FIG. 9F, FIG. 9G, FIG. 9H, FIG. 9I, FIG. 9J, FIG. 9K, FIG. 9L, FIG. 9M, FIG. 9N, FIG. 9O, FIG. 9P, FIG. 9Q, FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, FIG. 9V, FIG. 9W, FIG. 9X, FIG. 9Y, and FIG. 9Z. FIG. 9A is a cartoon of the contrast between the single transgene constructs (top) used in the virus mixing examples, and the dual transgene vectors used to make the E1/E3 transgene adenoviruses. FIG. 9B shows the results of mice injected i.t. with Empty virus+/-anti-PD-L1 or with TRZ-409 (IL-12/IL-7 dual transgene)+/-anti-PD-L1. The tumor volume of the injected tumor is shown in the left panel, and the tumor volume of the contralateral tumor is shown in the right panel. For each pair of arrows, the left arrow indicates virus injection and the right arrow indicates anti-PD-L1 injection. As can be seen for both the primary and contralateral tumors, TRZ-409 injection reduced tumor volume significantly compared to empty virus. The combination with anti-PD-L1 was slightly more efficacious in this study.

[0204] FIG. 9C shows the results of a second experiment using the inverse of TRZ-409, TRZ-403, in which the IL-7 transgene occupies the E1 region and the IL-12 gene occupies the E3 region (which has a stronger promoter than the E1). As can be seen in the Figure, TRZ-403 strongly inhibits primary and distant tumor growth, with or without anti-PD-L1. Plasma levels of IL-12 and IFN-.gamma. (FIG. 9D) for all mice injected with TRZ-403 show that expression of the transgenes is well tolerated.

[0205] The study was extended for all mice having tumors over 500 mm.sup.3. Mice having primary tumors injected with TRZ-403 (IL-7+IL-12), TRZ-403+anti-PD-L1, TRZ-403+control IgG, or TRZ-409 (IL-12+IL-7), and controls including untreated mice and mice injected with empty vector TRZ-d19K with anti-PD-L1, anti-PD-1, or a control IgG are shown in FIG. 9E, which illustrates the survival as a percentage of mice still on study. As can be seen in the FIG. 9E, mice injected with TRZ-403 had a much higher percentage of survival over TRZ-409 at the time end of the study (70 days). Both TRZ-403 and TRZ-409 showed efficacy over the controls; all mice receiving control injections were deceased by day 56 of the study.

[0206] Next, a direct comparison was made between the dual transgene virus TRZ-403 (Il-7+IL-12) and a mixture of IL-7 and IL-12 single transgene viruses. As can be seen in FIG. 9F, in the primary tumor (left panel) TRZ-403 showed the most efficacy in reducing tumor volume, followed by the mixture of viruses. The single transgene IL-12 virus showed a small amount of efficacy by comparison. In the contralateral tumor, however (right panel) only the dual transgene virus, TRZ-403, reduced the tumor volume, showing significant superiority over the mixture of viruses.

[0207] Viruses containing two transgenes in the E1 region were then tested. FIG. 9G, FIG. 9H, FIG. 9I, FIG. 9J, FIG. 9K, FIG. 9L, FIG. 9M, FIG. 9N, FIG. 9O, FIG. 9P, FIG. 9Q, FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, FIG. 9V, FIG. 9W, FIG. 9X, FIG. 9Y, and FIG. 9Z show comparisons of anti-tumor activity of various dual transgene viruses and controls, including comparison with antibody treatments. FIG. 9G, FIG. 9H, FIG. 9I, FIG. 9J, FIG. 9K, FIG. 9L, FIG. 9M, FIG. 9N, FIG. 9O, FIG. 9P, FIG. 9Q, FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, FIG. 9V, FIG. 9W, FIG. 9X, FIG. 9Y, and FIG. 9Z show the primary tumor in the left panel and the contralateral tumor in the right panel. All viruses were administered intratumorally and the antibodies were administered intraperitoneally. Viral dose regimens vary and are tabulated below in Table 7. FIG. 9G shows the tumor activity in untreated animal controls; FIG. 9H shows TRZ000 (E1-Empty/E3 Intact); FIG. 9I, FIG. 9J, and FIG. 9K show TRZ002 (E1-mIL-12/E3 Del); FIG. 9L, FIG. 9M, and FIG. 9N show TRZ510 (E1-mIL-7-P2A-mIL-12/E3 Del); FIG. 9O, FIG. 9P, and FIG. 9Q show TRZ021 (E1-empty/E3-mIL-2); FIG. 9R, FIG. 9S, FIG. 9T, FIG. 9U, and FIG. 9V show TRZ421 (E1-mIL-12/E3-mIL-2); FIG. 9W shows the combination of TRZ002 (E1-mIL-12/E3 Del)+Anti-CTLA4 antibody (see Table 7 for doses); FIG. 9X shows anti-PD-1 antibody treatment alone, FIG. 9Y shows anti-CTLA4 antibody alone, and FIG. 9Z shows results of treatment with the combination of anti-CTLA-4 and anti-PD-1 antibodies (both from BioXCell).

TABLE-US-00007 Shown # Dose (PFU/inj + in Mice Construct Route Schedule .mu.L/inj) FIG. 8 Untreated 9G 8 TRZ000 (E1-Empty/E3 Intact) IT Q4Dx3 1e9 9H 8 TRZ002 (E1-mIL-12/E3 Del) IT Q4Dx2 4e8 91 8 TRZ002 (E1-mIL-12/E3 Del) IT Q4Dx3 4e8 9J 8 TRZ002 (E1-mIL-12/E3 Del) IT Q4Dx3 1e9 9K 8 TRZ510 (E1-mIL-7-P2A-mIL-12/E3 IT Q4Dx2 4e8 9L Del) 8 TRZ510 (E1-mIL-7-P2A-mIL-12/E3 IT Q4Dx3 4e8 9M Del) 8 TRZ510 (E1-mIL-7-P2A-mIL-12/E3 IT Q4Dx3 1e9 9N Del) 8 TRZ021 (E1-empty/E3-mIL-2) IT Q4Dx2 4e8 90 8 TRZ021 (E1-empty/E3-mIL-2) IT Q4Dx3 4e8 9P 8 TRZ021 (E1-empty/E3-mIL-2) IT Q4Dx3 1e9 9Q 8 TRZ421 (E1-mIL-12/E3-mIL-2) IT Q4Dx1 4e8 9R 8 TRZ421 (E1-mIL-12/E3-mIL-2) IT Q4Dx2 4e8 9S 8 TRZ421 (E1-mIL-12/E3-mIL-2) IT Q4Dx3 4e8 9T 8 TRZ421 (E1-mIL-12/E3-mIL-2) IT Q4Dx2 1e9 9U 8 TRZ421 (E1-mIL-12/E3-mIL-2) IT Q4Dx3 1e9 9V 8 TRZ002 (E1-mIL-12/E3 Del) + Anti- IT + IP Q4Dx3 1e9 + 250 .mu.L 9W CTLA4 Ab + Q4Dx3; 1d post virus 8 Anti-PD-1 Ab IP Q4Dx3 250 .mu.L 9X 8 Anti-CTLA4 Ab IP Q4Dx3 250 .mu.L 9Y 8 Anti-CTLA4 Ab + Anti-PD-1 Ab IP Q4Dx3 250 .mu.L 9Z Dual constructs showed preliminary effectiveness at reducing tumor volume in mice, including TRZ421 and TRZ510.

Example 13. In Vitro Expression of Transgenes Cloned into E1 or E3 Site of Oncolytic Adenovirus

[0208] A549 cells (human lung adenocarcinoma, ATCC.RTM., cat #CCL-85.TM.) were grown in DMEM medium which is modified with 4.5 g/L D-glucose and 4 mM L-glutamine, and supplemented with 10% non-heat-inactivated fetal bovine serum (FBS) and 1% Penicillin/Streptomycin (P/S). The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C. ADS-12 cells (murine lung adenocarcinoma cell line) were grown in RPMI 1640 medium which is modified with 1% 100 mM Na pyruvate, 1% 200 mM L-glutamine, 1% 1M HEPES buffer, 1% of a 45% glucose solution and supplemented with 10% non-heat-inactivated Fetal Bovine Serum (FBS) and 1% 100.times. Penicillin/Streptomycin/L-Glutamine (PSG). The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C.

[0209] Sub-confluent A549 or ADS-12 cells were infected with TRZ000 (empty virus), TRZ510 (E1 IL-7-P2A-IL-12/E3), TRZ512 (E1 IL-12-P2A-IL-7/E3), TRZ403 (E1 IL-7/E3 IL-12), TRZ416 (E1 OX40L/E3 IL-12), or TRZ421 (E1 IL-12/E3 IL-2) at a multiplicity of infection (MOI) of 10 or 25. Forty-eight hours after infection, the supernatants were harvested, clarified by centrifugation, and assayed for protein expression by standard ELISA methods (mouse IL-12 (cat #M1270), mouse IL-2 (cat #M2000) and mouse IL-7 (cat #M7000) using Quantikine.RTM. kits, R&D Systems; mouse OX40L (cat #DY1236) using a DuoSet.RTM. kit, R&D Systems).

[0210] Results of measurement of secreted cytokines are shown in FIG. 10A FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F, and FIG. 10G. Expression of transgenes from the adenovirus E1 site is shown for IL-7 (FIG. 10A and FIG. 10B), OX40L (FIG. 10C), and IL-12 (FIG. 10D and FIG. 10E). Expression of transgenes from the E3 site is shown for IL-12 (FIG. 10F) and IL-2 (FIG. 10G). As can be seen in the Figures, all transgenes were expressed well from either the E1 or E3 site.

Example 14. In Vitro Functional Analysis of Transgenes Cloned into E1 or E3 Site of Oncolytic Adenovirus

[0211] A549 cells were grown in DMEM medium which is modified with 4.5 g/L D-glucose and 4 mM L-glutamine, and supplemented with 10% non-heat-inactivated fetal bovine serum (FBS) and 1% Penicillin/Streptomycin (P/S). The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C. In parallel, HEK-Blue.TM. IL-12 cells (modified human embryonic kidney (HEK) 293 cells; InvivoGen, cat #HKB-IL12) were grown in DMEM medium which is modified with 4.5 g/L D-glucose and 4 mM L-glutamine, and supplemented with 10% fetal bovine serum (FBS), 50 ng/ml of recombinant human IL-12 and 1% Penicillin/Streptomycin (P/S). The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C. CTLL-2 cells (mouse lymphocyte cells, ATCC.RTM., cat #TIB-214.TM.) were grown in RPMI medium which is modified with 2 mM glutamine, and supplemented with 10% fetal bovine serum (FBS), and 20 IU/ml human recombinant IL-2. The growth environment was maintained in an incubator with a 5% CO.sub.2 atmosphere at 37.degree. C.

[0212] Sub-confluent A549 cells were infected with TRZ510 (E1 IL-7-P2A-IL-12/E3), TRZ512 (E1 IL-12-P2A-IL-7/E3), TRZ403 (E1 IL-7/E3 IL-12), and TRZ416 (E1 OX40L/E3 IL-12) at a multiplicity of infection (MOI) of 10 or 25. Forty-eight hours after infection, the supernatants were harvested, clarified by centrifugation, and assayed for biological function of secreted IL-12 using HEK-Blue.TM. IL-12 cells. The HEK-Blue IL-12 cells were washed twice to remove excess recombinant human IL-12 and plated in each test well at 2.times.10.sup.5 cells/well in 180 .mu.L using 96-well round bottom plates. Serial dilutions of A549 supernatants from TRZ416-infected A549 cells were prepared at a 1:3 dilution and 20 .mu.L were added to the 180 .mu.L with HEK-Blue IL-12 cells. The last well with HEK-Blue IL-12 cells received 20 .mu.L of medium only as negative control. Twenty-four hours later 20 .mu.L of HEK-Blue IL-12 cell supernatant was added to 180 .mu.L of QUANTI-Blue.TM. (InvivoGen, cat #HKB-IL12) in a 96 well ELISA plate and incubated for 30 min at 37.degree. C. Secreted embryonic alkaline phosphatase (SEAP) levels were measured using a spectrophotometer at 620 nm. Alternatively, above described clarified supernatants from A549 cells were assayed for biological function of secreted IL-2 using CTLL-2 cells. CTLL-2 cells were washed twice to remove excess recombinant human IL-2 and plated in each test well at 5.times.10.sup.4 cells/well in 100 .mu.L using 96-well round bottom plates. Serial dilutions of A549 supernatants from TRZ421-infected A549 cells were prepared at a 1:3 dilution and 100 .mu.L were added to the 100 .mu.L with CTLL-2 cells. The last well with CTLL-2 cells received 100 .mu.L of medium only as negative control. Seventy-two hours later 100 .mu.L of CellTiter-Glo.RTM. (Promega, cat #G9241) was added to the induced CTLL-2 cells in 100 .mu.L and incubated for 10 min at room temperature. Combined CellTiter-Glo and CTLL-2 cells were transferred to a 96-well clear bottom plate for luminescence reading. Luminescence was recorded at an integration time of 0.5 sec/well.

[0213] Results of functional analysis of secreted cytokines are shown in FIG. 11A FIG. 11B, FIG. 11C, FIG. 11D, and FIG. 11E. Function of IL-12 transgenes in HEK-Blue IL-12 cells is shown for IL-12 in supernatants expressed from the E1 region (FIG. 11A, TRZ510; FIG. 11B, TRZ512) and from the E3 region (FIG. 11C; TRZ403; FIG. 11D; TRZ416). Function of IL-2 transgene in CTLL-2 cells is shown for supernatants expressed from the E3 region is shown in FIG. 11E (TRZ421). As can be seen in FIG. 11A FIG. 11B, FIG. 11C, FIG. 11D, and FIG. 11E, all transgenes were functional when expressed from the E1 or E3 sites, including those connected with a P2A sequence.

ENDNOTES

[0214] Although the invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[0215] All publications, databases, GenBank sequences, patents, and patent applications cited in this specification are herein incorporated by reference as if each specifically and individually indicated to be incorporated by reference.

TABLE-US-00008 APPENDIX A SEQUENCE REFERENCE Accession SEQ Number(s) ID or NO: Molecule description Sequence 1 hGITR-Ligand NP_005083 MTLHPSPITCEFLFSTALISPKMCLSHLENMPLSHSRTQGAQRS (GITR-L; SWKLWLFCSIVMLLFLCSFSWLIFIFLQLETAKEPCMAKFGPL TNFSF18) PSKWQMASSEPPCVNKVSDWKLEILQNGLYLIY GQVAPNANYNDVAPFEVRLYKNKDMIQTLTNKSKIQNVGGT YELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFIS 2 mGITR-Ligand NM_183391 MEEMPLRESSPQRAERCKKSWLLCIVALLLMLLCSLGTLIYTS (GITR-L; LKPTAIESCMVKFELSSSKWHMTSPKPHCVNTTSDGKLKILQS TNFSF18) GTYLIYGQVIPVDKKYIKDNAPFVVQIYKKNDVLQTLMNDFQ ILPIGGVYELHAGDNIYLKFNSKDHIQKTNTYWGIILMPDLPFI S 3 hCD28 ligand EAW79565 MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEV or agonist KEVATLSCGHNVSVEELAQTRIYWQKEKKMVLTMMSGDMN (CD80) IWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLK YEKDAFKREHLAEVTLSVKADFPTPSISDFEIPTSNIRRIICSTS GGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFN MTTNHSFMCLIKYGHLRVNQTFNWNTTKQEHFP DNLLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRES VRPV 4 hTNF.alpha. CAA78745 MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAG ATTLFCLLHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKP VAHVVANPQAEGQLQWLNRRANALLANGVELR DNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSY QTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKG DRLSAEINRPDYLDFAESGQVYFGIIAL 5 Non-cleavable NM_013693 MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAV mTNF.alpha. YLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEE MRRQFEDLVKDITLNKEEKKEDEDPVAHVVANHQVEEQLEW LSQRANALLANGMDLKDNQLVVPADGLYLVYSQVLFKGQG CPDYVLLTHTVSRFAISYQEKVNLLSAVKSPCPKDTPEGAELK PWYEPIYLGGVFQLEKGDQLSAEVNLPKYLDFAESGQVYFGII AL 6 mGM-CSF NM_009969 MWLQNLLFLGIVVYSLSAPTRSPITVTRPWKHVEAIKEALNLL DDMPVTLNEEVEVVSNEFSFKKLTCVQTRLKIFEQGLRGNFT KLKGALNMTASYYQTYCPPTPETDCETQVTTYADFIDSLKTF LTDIPFECKKPGQK 7 hICOS ligand NP_056074 MRLGSPGLLFLLFSSLRADTQEKEVRAMVGSDVELSCACPEG or agonist SRFDLNDVYVYWQTSESKTVVTYHIPQNSSLENVDSRYRNRA LMSPAGMLRGDFSLRLFNVTPQDEQKFHCLVLSQSL GFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTFTCTSING YPRPNVYWINKTDNSLLDQALQNDTVFLNMRGLYDVVSVLR IARTPSVNIGCCIENVLLQQNLTVGSQTGNDIGERD KITENPVSTGEKNAATWSILAVLCLLVVVAVAIGWVCRDRCL QHSYAGAWAVSPETELTGHV 8 h4-1BB ligand AAA53134 MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLL or agonist AAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAG LLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSL TGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSV SLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRL LHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRV TPEIPAGLPSPRSE 9 hOX40 ligand CAE11757 MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDR or agonist CCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKP CTWCNLRSGSERKQLCTATQDTVCRCRAGTQPLDSYK PGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSS DAICEDRDPPATQPQETQGPPARPITVQPTEAWPRTSQGPSTR PVEVPGGRAVAAILGLGLVLGLLGPLAILLALYLL RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI 10 mOX40 ligand NM_009452 MEGEGVQPLDENLENGSRPRFKWKKTLRLVVSGIKGAGMLL CFIYVCLQLSSSPAKDPPIQRLRGAVTRCEDGQLFISSYKNEYQ TMEVQNNSVVIKCDGLYITYLKGSFFQEVKIDLHFREDHNPISI PMLNDGRRIVFTVVASLAFKDKVYLTVNAPDTLCEHLQINDG ELIVVQLTPGYCAPEGSYHSTVNQVPL 11 hCD40 ligand NP_000065 MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAV or agonist YLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEI KSQFEGFVKDIMLNKEETKKENSFEMQKGDQNP QIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLT VKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILL RAANTHSSAKPCGQQSIHLGGVFELQPGASVFVN VTDPSQVSHGTGFTSFGLLKL 12 mCD40 ligand NM_011616 MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAV YLHRRLDKVEEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEE MRRQFEDLVKDITLNKEEKKENSFEMQRGDEDPQIAAHVVSE ANSNAASVLQWAKKGYYTMKSNLVMLENGKQLTVKREGLY YVYTQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTH SSSQLCEQQSVHLGGVFELQAGASVFVNVTEASQVIHRVGFS SFGLLKL 13 hCD27 ligand AAA36175 MPEEGSGCSVRRRPYGCVLRAALVPLVAGLVICLVVCIQRFA or agonist QAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALG RSFLHGPELDKGQLRIHRDGIYMVHIQVTLAICSSTTA SRHEIPTTLAVGICSPASRSISLLRLSFHQGCTIVSQRLTPLARG DTLCTNLTGTLLPSRNTDETFFGVQWVRP 14 mCD70 ligand NM_011617 MPEEGRPCPWVRWSGTAFQRQWPWLLLVVFITVFCCWFHCS or agonist GLLSKQQQRLLEHPEPHTAELQLNLTVPRKDPTLRWGAGPAL GRSFTHGPELEEGHLRIHQDGLYRLHIQVTLANCSSPGSTLQH RATLAVGICSPAAHGISLLRGRFGQDCTVALQRLTYLVHGDV LCTNLTLPLLPSRNADETFFGVQWICP 15 hInterleukin-2 AAB46883 MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQ (IL-2) MILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK PLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE TTFMCEYADETATIVEFLNRWITFCQSIISTLT 16 hInterleukin-7 AAH47698 MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMV (IL-7) SIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAAR KLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQ VKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQE IKTCWNKILMGTKEH 17 murine MM_008371.5 MFHVSFRYIFGIPPLILVLLPVTSSECHIKDKEGKAYESVLMISI Interleukin-7 DELDKMTGTDSNCPNNEPNFFRKHVCDDTKEAAFLNRAARK (IL-7) LKQFLKMNISEEFNVHLLTVSQGTQTLVNCTSKEEKNVKEQK KNDACFLKRLLREIKTCWNKILKGSI 18 Interleukin-12 AAD16432 MWPPGSASQPPPSPAAATGLHPAARPVSLQCRLSMCPARSLL (IL-12) alpha LVATLVLLDHLSLARNLPVATPDPGMFPCLHEISQNLLRAVSN subunit MLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACL PLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYED LKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQAL NFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMS YLNAS 19 hInterleukin-12 NP_005526 MEPLVTWVVPLLFLFLLSRQGAACRTSECCFQDPPYPDADSG (IL-12) SASGPRDLRCYRISSDRYECSWQYEGPTAGVSHFLRCCLSSGR receptor CCYFAAGSATRLQFSDQAGVSVLYTVTLWVESWAR subunit beta-1 NQTEKSPEVTLQLYNSVKYEPPLGDIKVSKLAGQLRMEWETP isoform DNQVGAEVQFRHRTPSSPWKLGDCGPQDDDTESCLCPLEMN precursor VAQEFQLRRRQLGSQGSSWSKWSSPVCVPPENPPQPQ VRFSVEQLGQDGRRRLTLKEQPTQLELPEGCQGLAPGTEVTY RLQLHMLSCPCKAKATRTLHLGKMPYLSGAAYNVAVISSNQ FGPGLNQTWHIPADTHTEPVALNISVGTNGTTMYWPA RAQSMTYCIEWQPVGQDGGLATCSLTAPQDPDPAGMATYSW SRESGAMGQEKCYYITIFASAHPEKLTLWSTVLSTYHFGGNA SAAGTPFIEWSVKNHSLDSVSVDWAPSLLSTCPGVLKE YVVRCRDEDSKQVSEHPVQPTETQVTLSGLRAGVAYTVQVR ADTAWLRGVWSQPQRFSIEVQVSDWLIFFASLGSFLSILLVGV LGYLGLNRAARHLCPPLPTPCASSAIEFPGGKETWQ WINPVDFQEEASLQEALVVEMSWDKGERTEPLEKTELPEGAP ELALDTELSLEDGDRCKAKM 20 murine N/A MCPQKLTISWFAIVLLVSPLMAMWELEKDVYVVEVDWTPDA Interleukin-12 PGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLD fusion AGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFL polypeptide KCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCG MASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALE ARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWE YPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLV EKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSG GGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKT AREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCL ATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQ AINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKP PVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSA 21 hIL-15 CAA62616 MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPK TEANWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTA MKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTES GCKECEELEEKNIKEFLQSFVHIVQMFINTS 22 mIL-15 hybrid N/A MKILKPYMRNTSISCYLCFLLNSHFLTEAGIHVFILGCVSVGLP KTEANWIDVRYDLEKIESLIQSIHIDTTLYTDSDFHPSCKVTAM NCFLLELQVILHEYSNMTLNETVRNVLYLANSTLSSNKNVAE SGCKECEELEEKTFTEFLQSFIRIVQMFINTSGSGATNFSLLKQ AGDVEENPGPGTTCPPPVSIEHADIRVKNYSVNSRERYVCNSG FKRKAGTSTLIECVINKNTNVAHWTTPSLKCIRDPSLAHYSPV PTVVTPKVTSQPESPSPSAKEPEAFSPKSDTAMTTETAIMPGSR LTPSQTTSAGTTGTGSHKSSRAPSLAATMTLEPTASTSLRITEIS PHSSKMTK 23 hIL-10 receptor NP_001549 MLPCLVVLLAALLSLRLGSDAHGTELPSPPSVWFEAEFFHHIL subunit alpha HWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAV precursor TLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSV DEVTLTVGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHF REYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEFCVQVKP SVASRSNKGMWSKEECISLTRQYFTVTNVIIFF AFVLLLSGALAYCLALQLYVRRRKKLPSVLLFKKPSPFIFISQR PSPETQDTIHPLDEEAFLKVSPELKNLDLHGSTDSGFGSTKPSL QTEEPQFLLPDPHPQADRTLGNREPPVLGDSC SSGSSNSTDSGICLQEPSLSPSTGPTWEQQVGSNSRGQDDSGID LVQNSEGRAGDTQGGSALGHHSPPEPEVPGEEDPAAVAFQGY LRQTRCAEEKATKTGCLEEESPLTDGLGPKFGRC LVDEAGLHPPALAKGYLKQDPLEMTLASSGAPTGQWNQPTE EWSLLALSSCSDLGISDWSFAHDLAPLGCVAAPGGLLGSFNS DLVTLPLISSLQSSE 24 mIL-10R Trap N/A MLSRLLPFLVTISSLSLEFIAYGTELPSPSYVWFEARFFQHILH WKPIPNQSESTYYEVALKQYGNSTWNDIHICRKAQALSCDLT TFTLDLYHRSYGYRARVRAVDNSQYSNWTTTETRFTVDEVIL TVDSVTLKAMDGIIYGTIHPPRPTITPAGDEYEQVFKDLRVYKI SIRKFSELKNATKRVKQETFTLTVPIGVRKFCVKVLPRLESRIN KAEWSEEQCLLITTEQYFTVTNLSHPASSTKVDKKIVPRDCGC KPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPE VQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWL NGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQ MAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIM DTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEK SLSHSPGK 25 hIL-27 NP_004834 MRGGRGAPFWLWPLPKLALLPLLWVLFQRTRPQGSAGPLQC Receptor YGVGPLGDLNCSWEPLGDLGAPSELHLQSQKYRSNKTQTVA subunit alpha VAAGRSWVAIPREQLTMSDKLLVWGTKAGQPLWPPVFV precursor NLETQMKPNAPRLGPDVDFSEDDPLEATVHWAPPTWPSHKV LICQFHYRRCQEAAWTLLEPELKTIPLTPVEIQDLELATGYKV YGRCRMEKEEDLWGEWSPILSFQTPPSAPKDVWVSG NLCGTPGGEEPLLLWKAPGPCVQVSYKVWFWVGGRELSPEG ITCCCSLIPSGAEWARVSAVNATSWEPLTNLSLVCLDSASAPR SVAVSSIAGSTELLVTWQPGPGEPLEHVVDWARDGD PLEKLNWVRLPPGNLSALLPGNFTVGVPYRITVTAVSASGLAS ASSVWGFREELAPLVGPTLWRLQDAPPGTPAIAWGEVPRHQL RGHLTHYTLCAQSGTSPSVCMNVSGNTQSVTLPDL PWGPCELWVTASTIAGQGPPGPILRLHLPDNTLRWKVLPGILF LWGLFLLGCGLSLATSGRCYHLRHKVLPRWVWEKVPDPANS SSGQPHMEQVPEAQPLGDLPILEVEEMEPPPVMESS QPAQATAPLDSGYEKHFLPTPEELGLLGPPRPQVLA 26 hIL-13 AAH96140 MVWSINLTAGMYCAALESLINVSGCSAIEKTQRMLSGFCPHK VSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN 27 hIL-17 AAC50341 MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRT VMVNLNIHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERY PSVIWEAKCRHLGCINADGNVDYHMNSVPIQQEIL VLRREPPHCPNSFRLEKILVSVGCTCVTPIVHHVA 28 hIL-33 NP_ MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCP Isoform a 001300974 MYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVL AACQQQSTVECFAFGISGVQKYTRALHDSSITGISPIT EYLASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSY YESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVE LHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFI GVKDNHLALIKVDSSENLCTENILFKLSET 29 hIL-33 NP_ MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCP Isoform a 001300973 MYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVL AACQQQSTVECFAFGISGVQKYTRALHDSSITGISPIT EYLASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSY YESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVE LHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFI GVKDNHLALIKVDSSENLCTENILFKLSET 30 hIL-33 NP_ MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCP

Isoform b 001186569 MYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVL AACQQQSTVECFAFGISGVQKYTRALHDSSITDKVLLS YYESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHS VELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKD NHLALIKVDSSENLCTENILFKLSET 31 hIL-33 NP_ MKPKMKYSTNKISTAKWKNTASKALCFKLGNKVLLSYYESQ Isoform c 001186570 HPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVELHK CEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKDNH LALIKVDSSENLCTENILFKLSET 32 hIL-33 NP_ MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCP Isoform d 001300975; MYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVL NP_ AACQQQSTVECFAFGISGVQKYTRALHDSSITEYLASL 001300976 STYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSYYESQHP SNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVELHKCE KPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKDNH LALIKVDSSENLCTENILFKLSET 33 hIL-33 NP_ MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCP Isoform e 001300977 MYFMKLRSGLMIKKEACYFRRETTKRPSLKTGISPITEYLASL STYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLS YYESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHS VELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKD NHLALIKVDSSENLCTENILFKLSET 34 hIFN-.gamma. AAB59534 MKYTSYILAFQLCIVLGSLGCYCQDPYVKEAENLKKYFNAGH SDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFKNFK DDQSIQKSVETIKEDMNVKFFNSNKKKRDDFEKLTN YSVTDLNVQRKAIHELIQVMAELSPAAKTGKRKRSQMLFRGR RASQ 35 Flagellin p06179 MAQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGLRINSAKD DAAGQAIANRFTANIKGLTQASRNANDGISIAQTTEGALNEIN NNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQ TQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDT LNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGT DQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKT NGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKA ALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYS ATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSI GGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALA QVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIEDSDY ATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR 36 anti-CTLA4 N/A MDMRVPAQLLGLLLLWLRGARCDIVMTQTTLSLPVSLGDQA (CTLA-4 SISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSG antagonist VPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGG antibody) GTKLEIKRADAAPTVSGSGGGSGGGSGGGSEAKLQESGPVLV KPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGVINP YNGDTSYNQKFKGKATLTVDKSSSTAYMELNSLTSEDSAVY YCARYYGSWFAYWGQGTLITVSTEPRGPTIKPCPPCKCPAPN LLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISW FVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKE FKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKK QVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDG SYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHEITTKSFSR TPGK 37 murine IL-2 DNA TATCACCCTTGCTAATCACTCCTCACAGTGACCTCAAGTCC (NM_008366.3) TGCAGGCATGTACAGCATGCAGCTCGCATCCTGTGTCACAT TGACACTTGTGCTCCTTGTCAACAGCGCACCCACTTCAAGC TCCACTTCAAGCTCTACAGCGGAAGCACAGCAGCAGCAGC AGCAGCAGCAGCAGCAGCAGCAGCACCTGGAGCAGCTGTT GATGGACCTACAGGAGCTCCTGAGCAGGATGGAGAATTAC AGGAACCTGAAACTCCCCAGGATGCTCACCTTCAAATTTTA CTTGCCCAAGCAGGCCACAGAATTGAAAGATCTTCAGTGC CTAGAAGATGAACTTGGACCTCTGCGGCATGTTCTGGATTT GACTCAAAGCAAAAGCTTTCAATTGGAAGATGCTGAGAAT TTCATCAGCAATATCAGAGTAACTGTTGTAAAACTAAAGG GCTCTGACAACACATTTGAGTGCCAATTCGATGATGAGTCA GCAACTGTGGTGGACTTTCTGAGGAGATGGATAGCCTTCTG TCAAAGCATCATCTCAACAAGCCCTCAATAACTATGTACCT CCTGCTTACAACACATAAGGCTCTCTATTTATTTAAATATT TAACTTTAATTTATTTTTGGATGTATTGTTTACTATCTTTTG TAACTACTAGTCTTCAGATGATAAATATGGATCTTTAAAGA TTCTTTTTGTAAGCCCCAAGGGCTCAAAAATGTTTTAAACT ATTTATCTGAAATTATTTATTATATTGAATTGTTAAATATCA TGTGTAGGTAGACTCATTAATAAAAGTATTTAGATGATTCA AATATAAATAAGCTCAGATGTCTGTCATTTTTAGGACAGCA CAAAGTAAGCGCTAAAATAACTTCTCAGTTATTCCTGTGAA CTCTATGTTAATCAGTGTTTTCAAGAAATAAAGCTCTCCTC TAAAAAAAAAAAAAAA 38 murine IL-2 amino acid MYSMQLASCVTLTLVLLVNSAPTSSSTSSSTAEAQQQQQQQQ CAA25909 QQQQHLEQLLMDLQELLSRMENYRNLKLPRMLTFKFYLPKQ ATELKDLQCLEDELGPLRHVLDLTQSKSFQLEDAENFISNIRV TVVKLKGSDNTFECQFDDESATVVDFLRRWIAFCQSIISTSPQ 39 murine Xcl1 DNA AGCCCAGCAAGACCTCAGCCATGAGACTTCTCCTCCTGACT (GenBank: TTCCTGGGAGTCTGCTGCCTCACCCCATGGGTTGTGGAAGG BC062249.1) TGTGGGGACTGAAGTCCTAGAAGAGAGTAGCTGTGTGAAC TTACAAACCCAGCGGCTGCCAGTTCAAAAAATCAAGACCT ATATCATCTGGGAGGGGGCCATGAGAGCTGTAATTTTTGTC ACCAAACGAGGACTAAAAATTTGTGCTGATCCAGAAGCCA AATGGGTGAAAGCAGCGATCAAGACTGTGGATGGCAGGGC CAGTACCAGAAAGAACATGGCTGAAACTGTTCCCACAGGA GCCCAGAGGTCCACCAGCACAGCGATAACCCTGACTGGGT AACAGCCTCCAGGACAATGTTTCCTCACTCGTTAAGCAGCT CATCTCAGTTCCCAAACCCATTGCACAAATACTTATTTTTA TTTTTAACGACATTCACATTCATTTCAAATGTTATAAGTAA TAAATATTTATTATTGATGAAAAAAAAAAAAAAAAAAAA 40 murine Xcl1 amino acid MRLLLLTFLGVCCLTPWVVEGVGTEVLEESSCVNLQTQRLPV (GenBank: QKIKTYIIWEGAMRAVIFVTKRGLKICADPEAKWVKAAIKTV BC062249.1) DGRASTRKNMAETVPTGAQRSTSTAITLTG 41 Murine 4- (DNA) GAGACGTGCACTGACCGACCGTGGTAATGGACCAGCACAC 1BBL GenBank: ACTTGATGTGGAGGATACCGCGGATGCCAGACATCCAGCA (TNFSF9) BC138767.1 GGTACTTCGTGCCCCTCGGATGCGGCGCTCCTCAGAGATA CCGGGCTCCTCGCGGACGCTGCGCTCCTCTCAGATACTGTG CGCCCCACAAATGCCGCGCTCCCCACGGATGCTGCCTACCC TGCGGTTAATGTTCGGGATCGCGAGGCCGCGTGGCCGCCT GCACTGAACTTCTGTTCCCGCCACCCAAAGCTCTATGGCCT AGTCGCTTTGGTTTTGCTGCTTCTGATCGCCGCCTGTGTTCC TATCTTCACCCGCACCGAGCCTCGGCCAGCGCTCACAATCA CCACCTCGCCCAACCTGGGTACCCGAGAGAATAATGCAGA CCAGGTCACCCCTGTTTCCCACATTGGCTGCCCCAACACTA CACAACAGGGCTCTCCTGTGTTCGCCAAGCTACTGGCTAAA AACCAAGCATCGTTGTGCAATACAACTCTGAACTGGCACA GCCAAGATGGAGCTGGGAGCTCATACCTATCTCAAGGTCT GAGGTACGAAGAAGACAAAAAGGAGTTGGTGGTAGACAG TCCCGGGCTCTACTACGTATTTTTGGAACTGAAGCTCAGTC CAACATTCACAAACACAGGCCACAAGGTGCAGGGCTGGGT CTCTCTTGTTTTGCAAGCAAAGCCTCAGGTAGATGACTTTG ACAACTTGGCCCTGACAGTGGAACTGTTCCCTTGCTCCATG GAGAACAAGTTAGTGGACCGTTCCTGGAGTCAACTGTTGC TCCTGAAGGCTGGCCACCGCCTCAGTGTGGGTCTGAGGGC TTATCTGCATGGAGCCCAGGATGCATACAGAGACTGGGAG CTGTCTTATCCCAACACCACCAGCTTTGGACTCTTTCTTGTG AAACCCGACAACCCATGGGAATGAGAACTATCCTTCTTGT GACTCCTAGTTGCTAAGTCCTCAAGCTGCTATGTTTTATGG GGTCTGAGCAGGGGT 42 Murine 4- (protein) MDQHTLDVEDTADARHPAGTSCPSDAALLRDTGLLADAALL 1BBL GenBank: SDTVRPTNAALPTDAAYPAVNVRDREAAWPPALNFCSRHPK (TNFSF9) BC138767.1 LYGLVALVLLLLIAACVPIFTRTEPRPALTITTSPNLGTRENNA DQVTPVSHIGCPNTTQQGSPVFAKLLAKNQASLCNTTLNWHS QDGAGSSYLSQGLRYEEDKKELVVDSPGLYYVFLELKLSPTF TNTGHKVQGWVSLVLQAKPQVDDFDNLALTVELFPCSMENK LVDRSWSQLLLLKAGHRLSVGLRAYLHGAQDAYRDWELSYP NTTSFGLFLVKPDNPWE 43 Mouse 4-1BBL with human MDMRVPAQLLGLLLLWLRGARCRMKQIEDKIEEILSKIYHIEN trimeric version IGKV1-39 EIARIKKLIGERGGGSGGGSGGGSRTEPRPALTITTSPNLGTRE kappa LC NNADQVTPVSHIGCPNTTQQGSPVFAKLLAKNQASLCNTTLN signal WHSQDGAGSSYLSQGLRYEEDKKELVVDSPGLYYVFLELKL sequence, SPTFTNTGHKVQGWVSLVLQAKPQVDDFDNLALTVELFPCS trimerization MENKLVDRSWSQLLLLKAGHRLSVGLRAYLHGAQDAYRDW domain from ELSYPNTTSFGLFLVKPDNPWE** yeast, and Linker 1, followed by 4-1BBL (TNFSF9, Acc# P41274) residues 104- 309 (minus ECD and transmembrane domain) 44 murine 4- residues 104- RTEPRPALTITTSPNLGTRENNADQVTPVSHIGCPNTTQQGSP 1BBL 209 (minus VFAKLLAKNQASLCNTTLNWHSQDGAGSSYLSQGLRYEEDK (TNFSF9, ECD and KELVVDSPGLYYVFLELKLSPTFTNTGHKVQGWVSLVLQAKP p41274) trans- QVDDFDNLALTVELFPCSMENKLVDRSWSQLLLLKAGHRLS membrane VGLRAYLHGAQDAYRDWELSYPNTTSFGLFLVKPDNPWE** domain) 45 Linker 1 15-mer GGGGSGGGGSGGGGS 46 TRZ202 (hIL- AA Sequence MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDA 12 Insert) PGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFG DAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKN KTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGV TCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEV MVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVE VSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTS ATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGG SGGGGSRNLPVATPDPGMFPCLIAHSQNLLRAVSNMLQKARQ TLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRE TSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNA KLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEE PDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS** 47 hIL-12 p40.beta. AF180563 MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDA PGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFG DAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKN KTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGV TCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEV MVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVE VSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTS ATVICRKNASISVRAQDRYYSSSWSEWASVPCS 48 hIL-12 p35.alpha. AA Sequence RNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPC of Accession TSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGS #AF 101062.1 CLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPK (native start RQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKI codon and KLCILLHAFRIRAVTIDRVMSYLNAS** signal sequence removed) 49 (TRZ015) AA GTCGACGCCACCMDMRVPAQLLGLLLLWLRGARCRMKQI hGITRL insert, Sequence, EDKIEEILSKIYHIENEIARIKKLIGERGGGSGGGSGGGSETAKE Trimeric including PCMAKFGPLPSKWQMASSEPPCVNKVSDWKLEILQNGLYLIY version Kozak GQVAPNANYNDVAPFEVRLYKNKDMIQTLTNKSKIQNVGGT sequences. YELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFIS** RE sites, and CTCGAG stop codons 50 hIGKV1-39 AA Sequence MDMRVPAQLLGLLLLWLRGARC kappa LC signal sequence 51 Trimerization AA Sequence RMKQIEDKIEEILSKIYHIENEIARIKKLIGER domain (yeast) 52 GITRL minus AA Sequence ETAKEPCMAKFGPLPSKWQMASSEPPCVNKVSDWKLEILQN ECD and GLYLIYGQVAPNANYNDVAPFEVRLYKNKDMIQTLTNKSKIQ transmembrane NVGGTYELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFIS** domains 53 Linker 2 12-mer GGGSGGGSGGGS 54 TRZ006:hIL- hIL-15R.alpha.- MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHAD 15 hybrid Linker-hIL- IWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAH 15 WTTPSLKCIRDPALVHQRPAPPSTVTTASGGSGGGGSGGGSG GGGSNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVT AMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTE SGCKECEELEEKNIKEFLQSFVHIVQMFINTS** 55 hIL-15R.alpha. AA Sequence MAPRRARGCRTLGLPALLLLLLLRPPATRG endogenous signal peptide 56 Sushi domain AA Sequence MSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLN from IL-15R.alpha. KATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTA 57 mature hIL-15 AA Sequence NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKC FLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCK ECEELEEKNIKEFLQSFVHIVQMFINTS 58 TRZ201: Orientation 2 MDMRVPAQLLGLLLLWLRGARCEIVLTQSPATLSLSPGERAT haCTLA4 ANT2054 LSCSASSSISYMHWFQQRPGQSPRRWIYDTSKLASGVPARFSG scFv-IgG1 Fc SGSGTDYTLTISSLEPEDFATYYCHQRTSYPLTFGQGTKLEIKG GGGSGGGGSGGGGSQVQLVQSGAELKKPGASVKVSCKASGY TFTSYWINWIRQAPGQGLEWIGRIAPGSGTTYYNEVFKGRVTI

TVDKSTSTAYMELSSLRSEDTAVYFCARGDYGSYWGQGTLV TVSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK** 59 Kappa variable AA Sequence EIVLTQSPATLSLSPGERATLSCSASSSISYMHWFQQRPGQSPR RWIYDTSKLASGVPARFSGSGSGTDYTLTISSLEPEDFATYYC HQRTSYPLTFGQGTKLEIK 60 Heavy variable AA Sequence QVQLVQSGAELKKPGASVKVSCKASGYTFTSYWINWIRQAP GQGLEWIGRIAPGSGTTYYNEVFKGRVTITVDKSTSTAYMEL SSLRSEDTAVYFCARGDYGSYWGQGTLVTVSS 61 human Fc IgG1 AA Sequence DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK** 62 TRZ106 hIL-15 MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHAD hybrid (hIL- IWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAH 15R.alpha.-Linker WTTPSLKCIRDPALVHQRPAPPSTVTTASGGSGGGGSGGGSG 2-hIL-15) GGGSNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVT (hIL-15R.alpha. AMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTE endogenous SGCKECEELEEKNIKEFLQSFVHIVQMFINTS** signal peptide, Sushi domain from IL- 15R.alpha., linker, mature hIL- 15) 63 hIL-15R.alpha. MAPRRARGCRTLGLPALLLLLLLRPPATRG endogenous signal peptide 64 mature hIL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKC FLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCK ECEELEEKNIKEFLQSFVHIVQMFINTS 65 TRZ108: full length MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAV hCD40 monomeric YLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEI version, KSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISE membrane ASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLY bound YIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHS SAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSF GLLKL** 66 TRZ111: full length MERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYI hOX40L monomeric CLHFSALQVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMK variant 1 version, VQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLK membrane KVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELI bound LIHQNPGEFCVL** 67 TRZ114: hIL- Extracellular MLPCLVVLLAALLSLRLGSDAHGTELPSPPSVWFEAEFFHHIL 10RTrap domain of HWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAV Version2 hIL-10R.alpha. TLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTV with GSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIR endogenous KVPGNFTFTHKKVKHENFSLLTSGEVGEFCVQVKPSVASRSN signal KGMWSKEECISLTRQYFTVTNDKTHTCPPCPAPELLGGPSVFL sequence, FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV without stop HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS and human NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC Fc IgG1 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK** 68 Extracellular HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRY domain of hIL- GIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGS 10R.alpha. RHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILGKIQLPRPK MAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSL LTSGEVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYFTVT N 69 endogenous MLPCLVVLLAALLSLRLGSDA signal sequence in TRZ114 70 human Fc IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK** 71 TRZ116: Trimeric MDMRVPAQLLGLLLLWLRGARCRMKQIEDKIEEILSKIYHIEN hOX40L version EIARIKKLIGERGGGSGGGSGGGSETAKEPCMAKFGPLPSKW w/human QMASSEPPCVNKVSDWKLEILQNGLYLIYGQVAPNANYNDV IGKV 1-39 APFEVRLYKNKDMIQTLTNKSKIQNVGGTYELHVGDTIDLIFN kappa LC SEHQVLKNNTYWGIILLANPQFIS** signal sequence, trimerization domain from yeast, and Linker 1, followed by OX40L minus ECD and trans- membrane domains 72 hOX40L minus QVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSV ECD and IINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNS transmembrane LMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGE domains FCVL** 73 TRZ117: Trimeric MDMRVPAQLLGLLLLWLRGARCRMKQIEDKIEEILSKIYHIEN hCD40L version EIARIKKLIGERGGGSGGGSGGGSMQKGDQNPQIAAHVISEAS w/human SKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIY IGKV 1-39 AQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAK kappa LC PCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLL signal KL** sequence, trimerization domain from yeast, and Linker 1, followed by CD40L minus ECD and trans- membrane domains 76 hCD40L minus MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLV ECD and TLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLK trans- SPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFV membrane domains NVTDPSQVSHGTGFTSFGLLKL** 77 TRZ307: hIL-7 MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMV variant 1 SIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAAR KLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAA LGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKIL MGTKEH** hIL-7 MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMV SIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAAR KLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAA LGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKIL MGTKEH** 78 TR2304: MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLL hGM-CSF NLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRG SLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLK DFLLVIPFDCWEPVQE** 79 hGM-C SF MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLL NLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRG SLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLK DFLLVIPFDCWEPVQE** 80 TRZ309: (residue in MPEEGSGCSVRRRPYGCVLRAALVPLVAGLVICLVVCIQRFA hCD70 bold to be QAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALG removed) RSFLHGPELDKGQLRIHRDGIYMVHIQVTLAICSSTTASRHHP TTLAVGICSPASRSISLLRLSFHQGCTIASQRLTPLARGDTLCT NLTGTLLPSRNTDETFFGVQWVRP** 81 hCD70 (residue in MPEEGSGCSVRRRPYGCVLRAALVPLVAGLVICLVVCIQRFA bold to be QAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALG modified to RSFLHGPELDKGQLRIHRDGIYMVHIQVTLAICSSTTASRHHP avoid TTLAVGICSPASRSISLLRLSFHQGCTIASQRLTPLARGDTLCT introducing NLTGTLLPSRNTDETFFGVQWVRP** new Xho I site) 82 E3 14.7k Region ATGACTGACACCCTAGATCTAGAAATGGACGGAATTATTA overlapping CAGAGCAGCGCCTGCTAGAAAGACGCAGGGCAGCGGCCG with E3 AGCAACAGCGCATGAATCAAGAGCTCCAAGACATGGTTAA 14.5k ORF in CTTGCACCAGTGCAAAAGGGGTATCTTTTGTCTGGTAAAGC bold AGGCCAAAGTCACCTACGACAGTAATACCACCGGACACCG CCTTAGCTACAAGTTGCCAACCAAGCGTCAGAAATTGGTG GTCATGGTGGGAGAAAAGCCCATTACCATAACTCAGCACT CGGTAGAAACCGAAGGCTGCATTCACTCACCTTGTCAAGG ACCTGAGGATCTCTGCACCCTTATTAAGACCCTGTGCGGTC TCAAAGATCTTATTCCCTTTAACTAA 83 E3 14.5k Region ATGAAATTTACTGTGACTTTTCTGCTGATTATTTGCACCCTA overlapping TCTGCGTTTTGTTCCCCGACCTCCAAGCCTCAAAGACATAT with E3 ATCATGCAGATTCACTCGTATATGGAATATTCCAAGTTGCT 14.7k in bold ACAATGAAAAAAGCGATCTTTCCGAAGCCTGGTTATATGC AATCATCTCTGTTATGGTGTTCTGCAGTACCATCTTAGCCC TAGCTATATATCCCTACCTTGACATTGGCTGGAACGCAATA GATGCCATGAACCACCCAACTTTCCCCGCGCCCGCTATGCT TCCACTGCAACAAGTTGTTGCCGGCGGCTTTGTCCCAGCCA ATCAGCCTCGCCCACCTTCTCCCACCCCCACTGAAATCAGC TACTTTAATCTAACAGGAGGAGATGACTGA 84 E3 10.4K ATGATTCCTCGAGTTTTTATATTACTGACCCTTGTTGCGCTT TTTTTGTGCGTGCTCCACATTGGCTGCGGTTTCTCACATCG AAGTAGACTGCATTCCAGCCTTCACAGTCTATTTGCTTTAC GGATTTGTCACCCTCACGCTCATCTGCAGCCTCATCACTGT GGTCATCGCCTTTATCCAGTGCATTGA 85 E3 10.5k ATGACCAACACAACCAACGCGGCCGCCGCTACCGGACTTA (ADP) CATCTACCACAAATACACCCCAAGTTTCTGCCTTTGTCAAT AACTGGGATAACTTGGGCATGTGGTGGTTCTCCATAGCGCT TATGTTTGTATGCCTTATTATTATGTGGCTCATCTGCTGCCT AAAGCGCAAACGCGCCCGACCACCCATCTATAGTCCCATC ATTGTGCTACACCCAAACAATGATGGAATCCATAGATTGG ACGGACTGAAACACATGTTCTTTTCTCTTACAGTATGA 86 TRZ000 intact Region ATGATTAGGTACATAATCCTAGGTTTACTCACCCTTGCGTC E3 gp19k ORF overlapping AGCCCACGGTACCACCCAAAAGGTGGATTTTAAGGAGCCA with E3 GCCTGTAATGTTACATTCGCAGCTGAAGCTAATGAGTGCAC gp19k ORF CACTCTTATAAAATGCACCACAGAACATGAAAAGCTGCTT in bold ATTCGCCACAAAAACAAAATTGGCAAGTATGCTGTTTATG CTATTTGGCAGCCAGGTGACACTACAGAGTATAATGTTAC AGTTTTCCAGGGTAAAAGTCATAAAACTTTTATGTATACTT TTCCATTTTATGAAATGTGCGACATTACCATGTACATGAGC AAACAGTATAAGTTGTGGCCCCCACAAAATTGTGTGGAAA ACACTGGCACTTTCTGCTGCACTGCTATGCTAATTACAGTG CTCGCTTTGGTCTGTACCCTACTCTATATTAAATACAAAAG CAGACGCAGCTTTATTGAGGAAAAGAAAATGCCTTAA 87 TRZ000 intact Region ATGAACAATTCAAGCAACTCTACGGGCTATTCTAATTCAGG E3 7.1K overlapping TTTCTCTAGAATCGGGGTTGGGGTTATTCTCTGTCTTGTGAT with E3 TCTCTTTATTCTTATACTAACGCTTCTCTGCCTAAGGCTCGC gp19k ORF CGCCTGCTGTGTGCACATTTGCATTTATTGTCAGCTTTTTAA in bold ACGCTGGGGTCGCCACCCAAGATGA 88 TRZ200 intact ATGTTAAGTGGAGAGGCAGAGCAACTGCGCCTGAAACACC E3 12.5k TGGTCCACTGTCGCCGCCACAAGTGCTTTGCCCGCGACTCC GGTGAGTTTTGCTACTTTGAATTGCCCGAGGATCATATCGA GGGCCCGGCGCACGGCGTCCGGCTTACCGCCCAGGGAGAG CTTGCCCGTAGCCTGATTCGGGAGTTTACCCAGCGCCCCCT GCTAGTTGAGCGGGACAGGGGACCCTGTGTTCTCACTGTG ATTTGCAACTGTCCTAACCCTGGATTACATCAAGATCTTTG TTGCCATCTCTGTGCTGAGTATAATAAATACAGAAATTAA 89 TRZ000 intact CACCCTAGATCTAGAAATGGACGGAATTATTACAGAGCAG E3 14.7k ORF CGCCTGCTAGAAAGACGCAGGGCAGCGGCCGAGCAACAG CGCATGAATCAAGAGCTCCAAGACATGGTTAACTTGCACC AGTGCAAAAGGGGTATCTTTTGTCTGGTAAAGCAGGCCAA AGTCACCTACGACAGTAATACCACCGGACACCGCCTTAGC TACAAGTTGCCAACCAAGCGTCAGAAATTGGTGGTCATGG TGGGAGAAAAGCCCATTACCATAACTCAGCACTCGGTAGA AACCGAAGGCTGCATTCACTCACCTTGTCAAGGACCTGAG GATCTCTGCACCCTTATTAAGACCCTGTGCGGTCTCAAAGA TCTTATTCCCTTTAACTAA 90 TRZ200 E3 AGACGCCCAGGCCGAAGTTCAGATGACTAACTCAGGGGCG region (not full CAGCTTGCGGGCGGCTTTCGTCACAGGGTGCGGTCGCCCG

E3-this is GGCAGGGTATAACTCACCTGACAATCAGAGGGCGAGGTAT deleted TCAGCTCAACGACGAGTCGGTGAGCTCCTCGCTTGGTCTCC version) GTCCGGACGGGACATTTCAGATCGGCGGCGCCGGCCGCTC TTCATTCACGCCTCGTCAGGCAATCCTAACTCTGCAGACCT CGTCCTCTGAGCCGCGCTCTGGAGGCATTGGAACTCTGCAA TTTATTGAGGAGTTTGTGCCATCGGTCTACTTTAACCCCTTC TCGGGACCTCCCGGCCACTATCCGGATCAATTTATTCCTAA CTTTGACGCGGTAAAGGACTCGGCGGACGGCTACGACTGA ATGTTAAGTGGAGAGGCAGAGCAACTGCGCCTGAAACACC TGGTCCACTGTCGCCGCCACAAGTGCTTTGCCCGCGACTCC GGTGAGTTTTGCTACTTTGAATTGCCCGAGGATCATATCGA GGGCCCGGCGCACGGCGTCCGGCTTACCGCCCAGGGAGAG CTTGCCCGTAGCCTGATTCGGGAGTTTACCCAGCGCCCCCT GCTAGTTGAGCGGGACAGGGGACCCTGTGTTCTCACTGTG ATTTGCAACTGTCCTAACCCTGGATTACATCAAGATCCTCT AGTTAATGTCAGGTCGCCTAAGTCGATTAACTAGAGTACCC GGGGATCTTATTCCCTTTAACTAA 91 TRZ200 GATCTTATTCCCTTTAACTAA deleted E3 14.7k partial ORF 92 TRZ200 ATGTTAAGTGGAGAGGCAGAGCAACTGCGCCTGAAACACC deleted E3 TGGTCCACTGTCGCCGCCACAAGTGCTTTGCCCGCGACTCC 12.5K partial GGTGAGTTTTGCTACTTTGAATTGCCCGAGGATCATATCGA ORF GGGCCCGGCGCACGGCGTCCGGCTTACCGCCCAGGGAGAG CTTGCCCGTAGCCTGATTCGGGAGTTTACCCAGCGCCCCCT GCTAGTTGAGCGGGACAGGGGACCCTGTGTTCTCACTGTG ATTTGCAACTGTCCTAACCCTGGATTACATCAAGAT 93 E3 Promoter AGACGCCCAGGCCGAAGTTCAGATGACTA (E3 deleted or E3 intact) 94 Full TRZ200 TTTTGGATTGAAGCCAATATGATAATGAGGGGGTGGAGTT virus sequence TGTGACGTGGCGCGGGGCGTGGGAACGGGGCGGGTGACGT beginning at 5' AGTAGTGTGGCGGAAGTGTGATGTTGCAAGTGTGGCGGAA ITR through 3' CACATGTAAGCGACGGATGTGGCAAAAGTGACGTTTTTGG ITR TGTGCGCCGGTGTTTTGGGCGTAACCGAGTAAGATTTGGCC ATTTTCGCGGGAAAACTGAATAAGAGGAAGTGAAATCTGA ATAATTTTGTGTTACTCATAGCGCGTAATATTTGTCTAGGG CCGCGGGGACTTTGACCGTTTACGTGGAGACTCGCCCAGG TGTTTTTCTCAGGTGTTTTCCGCGTTCCGGGTCAAAGTTGG CGTTTTATTATTATAGTCAGCTGACGTGTAGTGTATTTATA CCCGGTGAGTTCCTCAAGAGGCCACTCTTGAGTGCCAGCG AGTAGAGTTTTCTCCTCCGAGCCGCTCCGACACCGGGACTG AAAATGAGACATATTATCTGCCACGGAGGTGTTATTACCG AAGAAATGGCCGCCAGTCTTTTGGACCAGCTGATCGAAGA GGTACTGGCTGATAATCTTCCACCTCCTAGCCATTTTGAAC CACCTACCCTTCACGAACTGTATGATTTAGACGTGACGGCC CCCGAAGATCCCAACGAGGAGGCGGTTTCGCAGATTTTTC CCGACTCTGTAATGTTGGCGGTGCAGGAAGGGATTGACTT ACTCACTTTTCCGCCGGCGCCCGGTTCTCCGGAGCCGCCTC ACCTTTCCCGGCAGCCCGAGCAGCCGGAGCAGAGAGCCTT GGGTCCGGTTTCTATGCCAAACCTTGTACCGGAGGTGATCG ATCTTACCTGCCACGAGGCTGGCTTTCCACCCAGTGACGAC GAGGATGAAGAGGGTGAGGAGTTTGTGTTAGATTATGTGG AGCACCCCGGGCACGGTTGCAGGTCTTGTCATTATCACCGG AGGAATACGGGGGACCCAGATATTATGTGTTCGCTTTGCTA TATGAGGACCTGTGGCATGTTTGTCTACAGTAAGTGAAAAT TATGGGCAGTGGGTGATAGAGTGGTGGGTTTGGTGTGGTA ATTTTTTTTTTAATTTTTACAGTTTTGTGGTTTAAAGAATTT TGTATTGTGATTTTTTTAAAAGGTCCTGTGTCTGAACCTGA GCCTGAGCCCGAGCCAGAACCGGAGCCTGCAAGACCTACC CGCCGTCCTAAAATGGCGCCTGCTATCCTGAGACGCCCGA CATCACCTGTGTCTAGAGAATGCAATAGTAGTACGGATAG CTGTGACTCCGGTCCTTCTAACACACCTCCTGAGATACACC CGGTGGTCCCGCTGTGCCCCATTAAACCAGTTGCCGTGAGA GTTGGTGGGCGTCGCCAGGCTGTGGAATGTATCGAGGACT TGCTTAACGAGCCTGGGCAACCTTTGGACTTGAGCTGTAAA CGCCCCAGGCCATAAGGTGTAAACCTGTGATTGCGTGTGT GGTTAACGCCTTTGTTTGCTGAATGAGTTGATGTAAGTTTA ATAAAGGGTGAGATAATGTTTAACTTGCATGGCGTGTTAA ATGGGGCGGGGCTTAAAGGGTATATAATGCGCCGTGGGCT AATCTTGGTTACATCTGACCTCGTCGACGCTTGGGAGTGTT TGGAAGATTTTTCTGCTGTGCGTAACTTGCTGGAACAGAGC TCTAACAGTACCTCTTGGTTTTGGAGGTTTCTGTGGGGCTC ATCCCAGGCAAAGTTAGTCTGCAGAATTAAGGAGGATTAC AAGTGGGAATTTGAAGAGCTTTTGAAATCCTGTGGTGAGC TGTTTGATTCTTTGAACTCGAGTCACCAGGCGCTTTTCCAA GAGAAGGTCATCAAGACTTTGGATTTTTCCACACCGGGGC GCGCTGCGGCTGCTGTTGCTTTTTTGAGTTTTATAAAGGAT AAATGGAGCGAAGAAACCCATCTGAGCGGGGGGTACCTGC TGGATTTTCTGGCCATGCATCTGTGGAGAGCGGTTGTGAGA CACAAGAATCGCCTGCTACTGTTGTCTTCCGTCCGCCCGGC GATAATACCGACGGAGGAGCAGCAGCAGCAGCAGGAGGA AGCCAGGCGGCGGCGGCAGGAGCAGAGCCCATGGAACCC GAGAGCCGGCCTGGACCCTCGGGAATGAATGTTGTACAGG TGGCTGAACTGTATCCAGAACTGAGACGCATTTTGACAATT ACAGAGGATGGGCAGGGGCTAAAGGGGGTAAAGAGGGAG CGGGGGGCTTGTGAGGCTACAGAGGAGGCTAGGAATCTAG CTTTTAGCTTAATGACCAGACACCGTCCTGAGTGTATTACT TTTCAACAGATCAAGGATAATTGCGCTAATGAGCTTGATCT GCTGGCGCAGAAGTATTCCATAGAGCAGCTGACCACTTAC TGGCTGCAGCCAGGGGATGATTTTGAGGAGGCTATTAGGG TATATGCAAAGGTGGCACTTAGGCCAGATTGCAAGTACAA GATCAGCAAACTTGTAAATATCAGGAATTGTTGCTACATTT CTGGGAACGGGGCCGAGGTGGAGATAGATACGGAGGATA GGGTGGCCTTTAGATGTAGCATGATAAATATGTGGCCGGG GGTGCTTGGCATGGACGGGGTGGTTATTATGAATGTAAGG TTTACTGGCCCCAATTTTAGCGGTACGGTTTTCCTGGCCAA TACCAACCTTATCCTACACGGTGTAAGCTTCTATGGGTTTA ACAATACCTGTGTGGAAGCCTGGACCGATGTAAGGGTTCG GGGCTGTGCCTTTTACTGCTGCTGGAAGGGGGTGGTGTGTC GCCCCAAAAGCAGGGCTTCAATTAAGAAATGCCTCTTTGA AAGGTGTACCTTGGGTATCCTGTCTGAGGGTAACTCCAGG GTGCGCCACAATGTGGCCTCCGACTGTGGTTGCTTCATGCT AGTGAAAAGCGTGGCTGTGATTAAGCATAACATGGTATGT GGCAACTGCGAGGACAGGGCCTCTCAGATGCTGACCTGCT CGGACGGCAACTGTCACCTGCTGAAGACCATTCACGTAGC CAGCCACTCTCGCAAGGCCTGGCCAGTGTTTGAGCATAAC ATACTGACCCGCTGTTCCTTGCATTTGGGTAACAGGAGGGG GGTGTTCCTACCTTACCAATGCAATTTGAGTCACACTAAGA TATTGCTTGAGCCCGAGAGCATGTCCAAGGTGAACCTGAA CGGGGTGTTTGACATGACCATGAAGATCTGGAAGGTGCTG AGGTACGATGAGACCCGCACCAGGTGCAGACCCTGCGAGT GTGGCGGTAAACATATTAGGAACCAGCCTGTGATGCTGGA TGTGACCGAGGAGCTGAGGCCCGATCACTTGGTGCTGGCC TGCACCCGCGCTGAGTTTGGCTCTAGCGATGAAGATACAG ATTGAGGTACTGAAATGTGTGGGCGTGGCTTAAGGGTGGG AAAGAATATATAAGGTGGGGGTCTTATGTAGTTTTGTATCT GTTTTGCAGCAGCCGCCGCCGCCATGAGCACCAACTCGTTT GATGGAAGCATTGTGAGCTCATATTTGACAACGCGCATGC CCCCATGGGCCGGGGTGCGTCAGAATGTGATGGGCTCCAG CATTGATGGTCGCCCCGTCCTGCCCGCAAACTCTACTACCT TGACCTACGAGACCGTGTCTGGAACGCCGTTGGAGACTGC AGCCTCCGCCGCCGCTTCAGCCGCTGCAGCCACCGCCCGC GGGATTGTGACTGACTTTGCTTTCCTGAGCCCGCTTGCAAG CAGTGCAGCTTCCCGTTCATCCGCCCGCGATGACAAGTTGA CGGCTCTTTTGGCACAATTGGATTCTTTGACCCGGGAACTT AATGTCGTTTCTCAGCAGCTGTTGGATCTGCGCCAGCAGGT TTCTGCCCTGAAGGCTTCCTCCCCTCCCAATGCGGTTTAAA ACATAAATAAAAAACCAGACTCTGTTTGGATTTGGATCAA GCAAGTGTCTTGCTGTCTTTATTTAGGGGTTTTGCGCGCGC GGTAGGCCCGGGACCAGCGGTCTCGGTCGTTGAGGGTCCT GTGTATTTTTTCCAGGACGTGGTAAAGGTGACTCTGGATGT TCAGATACATGGGCATAAGCCCGTCTCTGGGGTGGAGGTA GCACCACTGCAGAGCTTCATGCTGCGGGGTGGTGTTGTAG ATGATCCAGTCGTAGCAGGAGCGCTGGGCGTGGTGCCTAA AAATGTCTTTCAGTAGCAAGCTGATTGCCAGGGGCAGGCC CTTGGTGTAAGTGTTTACAAAGCGGTTAAGCTGGGATGGG TGCATACGTGGGGATATGAGATGCATCTTGGACTGTATTTT TAGGTTGGCTATGTTCCCAGCCATATCCCTCCGGGGATTCA TGTTGTGCAGAACCACCAGCACAGTGTATCCGGTGCACTTG GGAAATTTGTCATGTAGCTTAGAAGGAAATGCGTGGAAGA ACTTGGAGACGCCCTTGTGACCTCCAAGATTTTCCATGCAT TCGTCCATAATGATGGCAATGGGCCCACGGGCGGCGGCCT GGGCGAAGATATTTCTGGGATCACTAACGTCATAGTTGTGT TCCAGGATGAGATCGTCATAGGCCATTTTTACAAAGCGCG GGCGGAGGGTGCCAGACTGCGGTATAATGGTTCCATCCGG CCCAGGGGCGTAGTTACCCTCACAGATTTGCATTTCCCACG CTTTGAGTTCAGATGGGGGGATCATGTCTACCTGCGGGGC GATGAAGAAAACGGTTTCCGGGGTAGGGGAGATCAGCTGG GAAGAAAGCAGGTTCCTGAGCAGCTGCGACTTACCGCAGC CGGTGGGCCCGTAAATCACACCTATTACCGGCTGCAACTG GTAGTTAAGAGAGCTGCAGCTGCCGTCATCCCTGAGCAGG GGGGCCACTTCGTTAAGCATGTCCCTGACTCGCATGTTTTC CCTGACCAAATCCGCCAGAAGGCGCTCGCCGCCCAGCGAT AGCAGTTCTTGCAAGGAAGCAAAGTTTTTCAACGGTTTGA GACCGTCCGCCGTAGGCATGCTTTTGAGCGTTTGACCAAGC AGTTCCAGGCGGTCCCACAGCTCGGTCACCTGCTCTACGGC ATCTCGATCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCG GCTTTCGCTGTACGGCAGTAGTCGGTGCTCGTCCAGACGGG CCAGGGTCATGTCTTTCCACGGGCGCAGGGTCCTCGTCAGC GTAGTCTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGCG CGCTGGCCAGGGTGCGCTTGAGGCTGGTCCTGCTGGTGCTG AAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGC ATTTGACCATGGTGTCATAGTCCAGCCCCTCCGCGGCGTGG CCCTTGGCGCGCAGCTTGCCCTTGGAGGAGGCGCCGCACG AGGGGCAGTGCAGACTTTTGAGGGCGTAGAGCTTGGGCGC GAGAAATACCGATTCCGGGGAGTAGGCATCCGCGCCGCAG GCCCCGCAGACGGTCTCGCATTCCACGAGCCAGGTGAGCT CTGGCCGTTCGGGGTCAAAAACCAGGTTTCCCCCATGCTTT TTGATGCGTTTCTTACCTCTGGTTTCCATGAGCCGGTGTCC ACGCTCGGTGACGAAAAGGCTGTCCGTGTCCCCGTATACA GACTTGAGAGGCCTGTCCTCGAGCGGTGTTCCGCGGTCCTC CTCGTATAGAAACTCGGACCACTCTGAGACAAAGGCTCGC GTCCAGGCCAGCACGAAGGAGGCTAAGTGGGAGGGGTAG CGGTCGTTGTCCACTAGGGGGTCCACTCGCTCCAGGGTGTG AAGACACATGTCGCCCTCTTCGGCATCAAGGAAGGTGATT GGTTTGTAGGTGTAGGCCACGTGACCGGGTGTTCCTGAAG GGGGGCTATAAAAGGGGGTGGGGGCGCGTTCGTCCTCACT CTCTTCCGCATCGCTGTCTGCGAGGGCCAGCTGTTGGGGTG AGTACTCCCTCTGAAAAGCGGGCATGACTTCTGCGCTAAG ATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCACCT GGCCCGCGGTGATGCCTTTGAGGGTGGCCGCATCCATCTG GTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGGTGGCAA ACGACCCGTAGAGGGCGTTGGACAGCAACTTGGCGATGGA GCGCAGGGTTTGGTTTTTGTCGCGATCGGCGCGCTCCTTGG CCGCGATGTTTAGCTGCACGTATTCGCGCGCAACGCACCGC CATTCGGGAAAGACGGTGGTGCGCTCGTCGGGCACCAGGT GCACGCGCCAACCGCGGTTGTGCAGGGTGACAAGGTCAAC GCTGGTGGCTACCTCTCCGCGTAGGCGCTCGTTGGTCCAGC AGAGGCGGCCGCCCTTGCGCGAGCAGAATGGCGGTAGGGG GTCTAGCTGCGTCTCGTCCGGGGGGTCTGCGTCCACGGTAA AGACCCCGGGCAGCAGGCGCGCGTCGAAGTAGTCTATCTT GCATCCTTGCAAGTCTAGCGCCTGCTGCCATGCGCGGGCG GCAAGCGCGCGCTCGTATGGGTTGAGTGGGGGACCCCATG GCATGGGGTGGGTGAGCGCGGAGGCGTACATGCCGCAAAT GTCGTAAACGTAGAGGGGCTCTCTGAGTATTCCAAGATAT GTAGGGTAGCATCTTCCACCGCGGATGCTGGCGCGCACGT AATCGTATAGTTCGTGCGAGGGAGCGAGGAGGTCGGGACC GAGGTTGCTACGGGCGGGCTGCTCTGCTCGGAAGACTATC TGCCTGAAGATGGCATGTGAGTTGGATGATATGGTTGGAC GCTGGAAGACGTTGAAGCTGGCGTCTGTGAGACCTACCGC GTCACGCACGAAGGAGGCGTAGGAGTCGCGCAGCTTGTTG ACCAGCTCGGCGGTGACCTGCACGTCTAGGGCGCAGTAGT CCAGGGTTTCCTTGATGATGTCATACTTATCCTGTCCCTTTT TTTTCCACAGCTCGCGGTTGAGGACAAACTCTTCGCGGTCT TTCCAGTACTCTTGGATCGGAAACCCGTCGGCCTCCGAACG GTAAGAGCCTAGCATGTAGAACTGGTTGACGGCCTGGTAG GCGCAGCATCCCTTTTCTACGGGTAGCGCGTATGCCTGCGC GGCCTTCCGGAGCGAGGTGTGGGTGAGCGCAAAGGTGTCC CTGACCATGACTTTGAGGTACTGGTATTTGAAGTCAGTGTC GTCGCATCCGCCCTGCTCCCAGAGCAAAAAGTCCGTGCGC TTTTTGGAACGCGGATTTGGCAGGGCGAAGGTGACATCGT TGAAGAGTATCTTTCCCGCGCGAGGCATAAAGTTGCGTGT GATGCGGAAGGGTCCCGGCACCTCGGAACGGTTGTTAATT ACCTGGGCGGCGAGCACGATCTCGTCAAAGCCGTTGATGT TGTGGCCCACAATGTAAAGTTCCAAGAAGCGCGGGATGCC CTTGATGGAAGGCAATTTTTTAAGTTCCTCGTAGGTGAGCT CTTCAGGGGAGCTGAGCCCGTGCTCTGAAAGGGCCCAGTC TGCAAGATGAGGGTTGGAAGCGACGAATGAGCTCCACAGG TCACGGGCCATTAGCATTTGCAGGTGGTCGCGAAAGGTCC TAAACTGGCGACCTATGGCCATTTTTTCTGGGGTGATGCAG TAGAAGGTAAGCGGGTCTTGTTCCCAGCGGTCCCATCCAA GGTTCGCGGCTAGGTCTCGCGCGGCAGTCACTAGAGGCTC ATCTCCGCCGAACTTCATGACCAGCATGAAGGGCACGAGC TGCTTCCCAAAGGCCCCCATCCAAGTATAGGTCTCTACATC GTAGGTGACAAAGAGACGCTCGGTGCGAGGATGCGAGCCG ATCGGGAAGAACTGGATCTCCCGCCACCAATTGGAGGAGT GGCTATTGATGTGGTGAAAGTAGAAGTCCCTGCGACGGGC CGAACACTCGTGCTGGCTTTTGTAAAAACGTGCGCAGTACT GGCAGCGGTGCACGGGCTGTACATCCTGCACGAGGTTGAC CTGACGACCGCGCACAAGGAAGCAGAGTGGGAATTTGAGC CCCTCGCCTGGCGGGTTTGGCTGGTGGTCTTCTACTTCGGC TGCTTGTCCTTGACCGTCTGGCTGCTCGAGGGGAGTTACGG TGGATCGGACCACCACGCCGCGCGAGCCCAAAGTCCAGAT GTCCGCGCGCGGCGGTCGGAGCTTGATGACAACATCGCGC AGATGGGAGCTGTCCATGGTCTGGAGCTCCCGCGGCGTCA GGTCAGGCGGGAGCTCCTGCAGGTTTACCTCGCATAGACG GGTCAGGGCGCGGGCTAGATCCAGGTGATACCTAATTTCC AGGGGCTGGTTGGTGGCGGCGTCGATGGCTTGCAAGAGGC CGCATCCCCGCGGCGCGACTACGGTACCGCGCGGCGGGCG GTGGGCCGCGGGGGTGTCCTTGGATGATGCATCTAAAAGC GGTGACGCGGGCGAGCCCCCGGAGGTAGGGGGGGCTCCG GACCCGCCGGGAGAGGGGGCAGGGGCACGTCGGCGCCGC GCGCGGGCAGGAGCTGGTGCTGCGCGCGTAGGTTGCTGGC GAACGCGACGACGCGGCGGTTGATCTCCTGAATCTGGCGC CTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAACCTGA

AAGAGAGTTCGACAGAATCAATTTCGGTGTCGTTGACGGC GGCCTGGCGCAAAATCTCCTGCACGTCTCCTGAGTTGTCTT GATAGGCGATCTCGGCCATGAACTGCTCGATCTCTTCCTCC TGGAGATCTCCGCGTCCGGCTCGCTCCACGGTGGCGGCGA GGTCGTTGGAAATGCGGGCCATGAGCTGCGAGAAGGCGTT GAGGCCTCCCTCGTTCCAGACGCGGCTGTAGACCACGCCC CCTTCGGCATCGCGGGCGCGCATGACCACCTGCGCGAGAT TGAGCTCCACGTGCCGGGCGAAGACGGCGTAGTTTCGCAG GCGCTGAAAGAGGTAGTTGAGGGTGGTGGCGGTGTGTTCT GCCACGAAGAAGTACATAACCCAGCGTCGCAACGTGGATT CGTTGATATCCCCCAAGGCCTCAAGGCGCTCCATGGCCTCG TAGAAGTCCACGGCGAAGTTGAAAAACTGGGAGTTGCGCG CCGACACGGTTAACTCCTCCTCCAGAAGACGGATGAGCTC GGCGACAGTGTCGCGCACCTCGCGCTCAAAGGCTACAGGG GCCTCTTCTTCTTCTTCAATCTCCTCTTCCATAAGGGCCTCC CCTTCTTCTTCTTCTGGCGGCGGTGGGGGAGGGGGGACAC GGCGGCGACGACGGCGCACCGGGAGGCGGTCGACAAAGC GCTCGATCATCTCCCCGCGGCGACGGCGCATGGTCTCGGTG ACGGCGCGGCCGTTCTCGCGGGGGCGCAGTTGGAAGACGC CGCCCGTCATGTCCCGGTTATGGGTTGGCGGGGGGCTGCC ATGCGGCAGGGATACGGCGCTAACGATGCATCTCAACAAT TGTTGTGTAGGTACTCCGCCGCCGAGGGACCTGAGCGAGT CCGCATCGACCGGATCGGAAAACCTCTCGAGAAAGGCGTC TAACCAGTCACAGTCGCAAGGTAGGCTGAGCACCGTGGCG GGCGGCAGCGGGCGGCGGTCGGGGTTGTTTCTGGCGGAGG TGCTGCTGATGATGTAATTAAAGTAGGCGGTCTTGAGACG GCGGATGGTCGACAGAAGCACCATGTCCTTGGGTCCGGCC TGCTGAATGCGCAGGCGGTCGGCCATGCCCCAGGCTTCGTT TTGACATCGGCGCAGGTCTTTGTAGTAGTCTTGCATGAGCC TTTCTACCGGCACTTCTTCTTCTCCTTCCTCTTGTCCTGCAT CTCTTGCATCTATCGCTGCGGCGGCGGCGGAGTTTGGCCGT AGGTGGCGCCCTCTTCCTCCCATGCGTGTGACCCCGAAGCC CCTCATCGGCTGAAGCAGGGCTAGGTCGGCGACAACGCGC TCGGCTAATATGGCCTGCTGCACCTGCGTGAGGGTAGACT GGAAGTCATCCATGTCCACAAAGCGGTGGTATGCGCCCGT GTTGATGGTGTAAGTGCAGTTGGCCATAACGGACCAGTTA ACGGTCTGGTGACCCGGCTGCGAGAGCTCGGTGTACCTGA GACGCGAGTAAGCCCTCGAGTCAAATACGTAGTCGTTGCA AGTCCGCACCAGGTACTGGTATCCCACCAAAAAGTGCGGC GGCGGCTGGCGGTAGAGGGGCCAGCGTAGGGTGGCCGGG GCTCCGGGGGCGAGATCTTCCAACATAAGGCGATGATATC CGTAGATGTACCTGGACATCCAGGTGATGCCGGCGGCGGT GGTGGAGGCGCGCGGAAAGTCGCGGACGCGGTTCCAGATG TTGCGCAGCGGCAAAAAGTGCTCCATGGTCGGGACGCTCT GGCCGGTCAGGCGCGCGCAATCGTTGACGCTCTAGCGTGC AAAAGGAGAGCCTGTAAGCGGGCACTCTTCCGTGGTCTGG TGGATAAATTCGCAAGGGTATCATGGCGGACGACCGGGGT TCGAGCCCCGTATCCGGCCGTCCGCCGTGATCCATGCGGTT ACCGCCCGCGTGTCGAACCCAGGTGTGCGACGTCAGACAA CGGGGGAGTGCTCCTTTTGGCTTCCTTCCAGGCGCGGCGGC TGCTGCGCTAGCTTTTTTGGCCACTGGCCGCGCGCAGCGTA AGCGGTTAGGCTGGAAAGCGAAAGCATTAAGTGGCTCGCT CCCTGTAGCCGGAGGGTTATTTTCCAAGGGTTGAGTCGCGG GACCCCCGGTTCGAGTCTCGGACCGGCCGGACTGCGGCGA ACGGGGGTTTGCCTCCCCGTCATGCAAGACCCCGCTTGCAA ATTCCTCCGGAAACAGGGACGAGCCCCTTTTTTGCTTTTCC CAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCTCCTCA GCAGCGGCAAGAGCAAGAGCAGCGGCAGACATGCAGGGC ACCCTCCCCTCCTCCTACCGCGTCAGGAGGGGCGACATCCG CGGTTGACGCGGCAGCAGATGGTGATTACGAACCCCCGCG GCGCCGGGCCCGGCACTACCTGGACTTGGAGGAGGGCGAG GGCCTGGCGCGGCTAGGAGCGCCCTCTCCTGAGCGGCACC CAAGGGTGCAGCTGAAGCGTGATACGCGTGAGGCGTACGT GCCGCGGCAGAACCTGTTTCGCGACCGCGAGGGAGAGGAG CCCGAGGAGATGCGGGATCGAAAGTTCCACGCAGGGCGCG AGCTGCGGCATGGCCTGAATCGCGAGCGGTTGCTGCGCGA GGAGGACTTTGAGCCCGACGCGCGAACCGGGATTAGTCCC GCGCGCGCACACGTGGCGGCCGCCGACCTGGTAACCGCAT ACGAGCAGACGGTGAACCAGGAGATTAACTTTCAAAAAAG CTTTAACAACCACGTGCGTACGCTTGTGGCGCGCGAGGAG GTGGCTATAGGACTGATGCATCTGTGGGACTTTGTAAGCGC GCTGGAGCAAAACCCAAATAGCAAGCCGCTCATGGCGCAG CTGTTCCTTATAGTGCAGCACAGCAGGGACAACGAGGCAT TCAGGGATGCGCTGCTAAACATAGTAGAGCCCGAGGGCCG CTGGCTGCTCGATTTGATAAACATCCTGCAGAGCATAGTGG TGCAGGAGCGCAGCTTGAGCCTGGCTGACAAGGTGGCCGC CATCAACTATTCCATGCTTAGCCTGGGCAAGTTTTACGCCC GCAAGATATACCATACCCCTTACGTTCCCATAGACAAGGA GGTAAAGATCGAGGGGTTCTACATGCGCATGGCGCTGAAG GTGCTTACCTTGAGCGACGACCTGGGCGTTTATCGCAACGA GCGCATCCACAAGGCCGTGAGCGTGAGCCGGCGGCGCGAG CTCAGCGACCGCGAGCTGATGCACAGCCTGCAAAGGGCCC TGGCTGGCACGGGCAGCGGCGATAGAGAGGCCGAGTCCTA CTTTGACGCGGGCGCTGACCTGCGCTGGGCCCCAAGCCGA CGCGCCCTGGAGGCAGCTGGGGCCGGACCTGGGCTGGCGG TGGCACCCGCGCGCGCTGGCAACGTCGGCGGCGTGGAGGA ATATGACGAGGACGATGAGTACGAGCCAGAGGACGGCGA GTACTAAGCGGTGATGTTTCTGATCAGATGATGCAAGACG CAACGGACCCGGCGGTGCGGGCGGCGCTGCAGAGCCAGCC GTCCGGCCTTAACTCCACGGACGACTGGCGCCAGGTCATG GACCGCATCATGTCGCTGACTGCGCGCAATCCTGACGCGTT CCGGCAGCAGCCGCAGGCCAACCGGCTCTCCGCAATTCTG GAAGCGGTGGTCCCGGCGCGCGCAAACCCCACGCACGAGA AGGTGCTGGCGATCGTAAACGCGCTGGCCGAAAACAGGGC CATCCGGCCCGACGAGGCCGGCCTGGTCTACGACGCGCTG CTTCAGCGCGTGGCTCGTTACAACAGCGGCAACGTGCAGA CCAACCTGGACCGGCTGGTGGGGGATGTGCGCGAGGCCGT GGCGCAGCGTGAGCGCGCGCAGCAGCAGGGCAACCTGGG CTCCATGGTTGCACTAAACGCCTTCCTGAGTACACAGCCCG CCAACGTGCCGCGGGGACAGGAGGACTACACCAACTTTGT GAGCGCACTGCGGCTAATGGTGACTGAGACACCGCAAAGT GAGGTGTACCAGTCTGGGCCAGACTATTTTTTCCAGACCAG TAGACAAGGCCTGCAGACCGTAAACCTGAGCCAGGCTTTC AAAAACTTGCAGGGGCTGTGGGGGGTGCGGGCTCCCACAG GCGACCGCGCGACCGTGTCTAGCTTGCTGACGCCCAACTC GCGCCTGTTGCTGCTGCTAATAGCGCCCTTCACGGACAGTG GCAGCGTGTCCCGGGACACATACCTAGGTCACTTGCTGAC ACTGTACCGCGAGGCCATAGGTCAGGCGCATGTGGACGAG CATACTTTCCAGGAGATTACAAGTGTCAGCCGCGCGCTGG GGCAGGAGGACACGGGCAGCCTGGAGGCAACCCTAAACT ACCTGCTGACCAACCGGCGGCAGAAGATCCCCTCGTTGCA CAGTTTAAACAGCGAGGAGGAGCGCATTTTGCGCTACGTG CAGCAGAGCGTGAGCCTTAACCTGATGCGCGACGGGGTAA CGCCCAGCGTGGCGCTGGACATGACCGCGCGCAACATGGA ACCGGGCATGTATGCCTCAAACCGGCCGTTTATCAACCGCC TAATGGACTACTTGCATCGCGCGGCCGCCGTGAACCCCGA GTATTTCACCAATGCCATCTTGAACCCGCACTGGCTACCGC CCCCTGGTTTCTACACCGGGGGATTCGAGGTGCCCGAGGG TAACGATGGATTCCTCTGGGACGACATAGACGACAGCGTG TTTTCCCCGCAACCGCAGACCCTGCTAGAGTTGCAACAGCG CGAGCAGGCAGAGGCGGCGCTGCGAAAGGAAAGCTTCCG CAGGCCAAGCAGCTTGTCCGATCTAGGCGCTGCGGCCCCG CGGTCAGATGCTAGTAGCCCATTTCCAAGCTTGATAGGGTC TCTTACCAGCACTCGCACCACCCGCCCGCGCCTGCTGGGCG AGGAGGAGTACCTAAACAACTCGCTGCTGCAGCCGCAGCG CGAAAAAAACCTGCCTCCGGCATTTCCCAACAACGGGATA GAGAGCCTAGTGGACAAGATGAGTAGATGGAAGACGTAC GCGCAGGAGCACAGGGACGTGCCAGGCCCGCGCCCGCCCA CCCGTCGTCAAAGGCACGACCGTCAGCGGGGTCTGGTGTG GGAGGACGATGACTCGGCAGACGACAGCAGCGTCCTGGAT TTGGGAGGGAGTGGCAACCCGTTTGCGCACCTTCGCCCCA GGCTGGGGAGAATGTTTTAAAAAAAAAAAAGCATGATGCA AAATAAAAAACTCACCAAGGCCATGGCACCGAGCGTTGGT TTTCTTGTATTCCCCTTAGTATGCGGCGCGCGGCGATGTAT GAGGAAGGTCCTCCTCCCTCCTACGAGAGTGTGGTGAGCG CGGCGCCAGTGGCGGCGGCGCTGGGTTCTCCCTTCGATGCT CCCCTGGACCCGCCGTTTGTGCCTCCGCGGTACCTGCGGCC TACCGGGGGGAGAAACAGCATCCGTTACTCTGAGTTGGCA CCCCTATTCGACACCACCCGTGTGTACCTGGTGGACAACAA GTCAACGGATGTGGCATCCCTGAACTACCAGAACGACCAC AGCAACTTTCTGACCACGGTCATTCAAAACAATGACTACA GCCCGGGGGAGGCAAGCACACAGACCATCAATCTTGACGA CCGGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCAT ACCAACATGCCAAATGTGAACGAGTTCATGTTTACCAATA AGTTTAAGGCGCGGGTGATGGTGTCGCGCTTGCCTACTAA GGACAATCAGGTGGAGCTGAAATACGAGTGGGTGGAGTTC ACGCTGCCCGAGGGCAACTACTCCGAGACCATGACCATAG ACCTTATGAACAACGCGATCGTGGAGCACTACTTGAAAGT GGGCAGACAGAACGGGGTTCTGGAAAGCGACATCGGGGT AAAGTTTGACACCCGCAACTTCAGACTGGGGTTTGACCCC GTCACTGGTCTTGTCATGCCTGGGGTATATACAAACGAAGC CTTCCATCCAGACATCATTTTGCTGCCAGGATGCGGGGTGG ACTTCACCCACAGCCGCCTGAGCAACTTGTTGGGCATCCGC AAGCGGCAACCCTTCCAGGAGGGCTTTAGGATCACCTACG ATGATCTGGAGGGTGGTAACATTCCCGCACTGTTGGATGTG GACGCCTACCAGGCGAGCTTGAAAGATGACACCGAACAGG GCGGGGGTGGCGCAGGCGGCAGCAACAGCAGTGGCAGCG GCGCGGAAGAGAACTCCAACGCGGCAGCCGCGGCAATGC AGCCGGTGGAGGACATGAACGATCATGCCATTCGCGGCGA CACCTTTGCCACACGGGCTGAGGAGAAGCGCGCTGAGGCC GAAGCAGCGGCCGAAGCTGCCGCCCCCGCTGCGCAACCCG AGGTCGAGAAGCCTCAGAAGAAACCGGTGATCAAACCCCT GACAGAGGACAGCAAGAAACGCAGTTACAACCTAATAAG CAATGACAGCACCTTCACCCAGTACCGCAGCTGGTACCTTG CATACAACTACGGCGACCCTCAGACCGGAATCCGCTCATG GACCCTGCTTTGCACTCCTGACGTAACCTGCGGCTCGGAGC AGGTCTACTGGTCGTTGCCAGACATGATGCAAGACCCCGT GACCTTCCGCTCCACGCGCCAGATCAGCAACTTTCCGGTGG TGGGCGCCGAGCTGTTGCCCGTGCACTCCAAGAGCTTCTAC AACGACCAGGCCGTCTACTCCCAACTCATCCGCCAGTTTAC CTCTCTGACCCACGTGTTCAATCGCTTTCCCGAGAACCAGA TTTTGGCGCGCCCGCCAGCCCCCACCATCACCACCGTCAGT GAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGC TGCGCAACAGCATCGGAGGAGTCCAGCGAGTGACCATTAC TGACGCCAGACGCCGCACCTGCCCCTACGTTTACAAGGCC CTGGGCATAGTCTCGCCGCGCGTCCTATCGAGCCGCACTTT TTGAGCAAGCATGTCCATCCTTATATCGCCCAGCAATAACA CAGGCTGGGGCCTGCGCTTCCCAAGCAAGATGTTTGGCGG GGCCAAGAAGCGCTCCGACCAACACCCAGTGCGCGTGCGC GGGCACTACCGCGCGCCCTGGGGCGCGCACAAACGCGGCC GCACTGGGCGCACCACCGTCGATGACGCCATCGACGCGGT GGTGGAGGAGGCGCGCAACTACACGCCCACGCCGCCACCA GTGTCCACAGTGGACGCGGCCATTCAGACCGTGGTGCGCG GAGCCCGGCGCTATGCTAAAATGAAGAGACGGCGGAGGC GCGTAGCACGTCGCCACCGCCGCCGACCCGGCACTGCCGC CCAACGCGCGGCGGCGGCCCTGCTTAACCGCGCACGTCGC ACCGGCCGACGGGCGGCCATGCGGGCCGCTCGAAGGCTGG CCGCGGGTATTGTCACTGTGCCCCCCAGGTCCAGGCGACG AGCGGCCGCCGCAGCAGCCGCGGCCATTAGTGCTATGACT CAGGGTCGCAGGGGCAACGTGTATTGGGTGCGCGACTCGG TTAGCGGCCTGCGCGTGCCCGTGCGCACCCGCCCCCCGCGC AACTAGATTGCAAGAAAAAACTACTTAGACTCGTACTGTT GTATGTATCCAGCGGCGGCGGCGCGCAACGAAGCTATGTC CAAGCGCAAAATCAAAGAAGAGATGCTCCAGGTCATCGCG CCGGAGATCTATGGCCCCCCGAAGAAGGAAGAGCAGGATT ACAAGCCCCGAAAGCTAAAGCGGGTCAAAAAGAAAAAGA AAGATGATGATGATGAACTTGACGACGAGGTGGAACTGCT GCACGCTACCGCGCCCAGGCGACGGGTACAGTGGAAAGGT CGACGCGTAAAACGTGTTTTGCGACCCGGCACCACCGTAG TCTTTACGCCCGGTGAGCGCTCCACCCGCACCTACAAGCGC GTGTATGATGAGGTGTACGGCGACGAGGACCTGCTTGAGC AGGCCAACGAGCGCCTCGGGGAGTTTGCCTACGGAAAGCG GCATAAGGACATGCTGGCGTTGCCGCTGGACGAGGGCAAC CCAACACCTAGCCTAAAGCCCGTAACACTGCAGCAGGTGC TGCCCGCGCTTGCACCGTCCGAAGAAAAGCGCGGCCTAAA GCGCGAGTCTGGTGACTTGGCACCCACCGTGCAGCTGATG GTACCCAAGCGCCAGCGACTGGAAGATGTCTTGGAAAAAA TGACCGTGGAACCTGGGCTGGAGCCCGAGGTCCGCGTGCG GCCAATCAAGCAGGTGGCGCCGGGACTGGGCGTGCAGACC GTGGACGTTCAGATACCCACTACCAGTAGCACCAGTATTG CCACCGCCACAGAGGGCATGGAGACACAAACGTCCCCGGT TGCCTCAGCGGTGGCGGATGCCGCGGTGCAGGCGGTCGCT GCGGCCGCGTCCAAGACCTCTACGGAGGTGCAAACGGACC CGTGGATGTTTCGCGTTTCAGCCCCCCGGCGCCCGCGCCGT TCGAGGAAGTACGGCGCCGCCAGCGCGCTACTGCCCGAAT ATGCCCTACATCCTTCCATTGCGCCTACCCCCGGCTATCGT GGCTACACCTACCGCCCCAGAAGACGAGCAACTACCCGAC GCCGAACCACCACTGGAACCCGCCGCCGCCGTCGCCGTCG CCAGCCCGTGCTGGCCCCGATTTCCGTGCGCAGGGTGGCTC GCGAAGGAGGCAGGACCCTGGTGCTGCCAACAGCGCGCTA CCACCCCAGCATCGTTTAAAAGCCGGTCTTTGTGGTTCTTG CAGATATGGCCCTCACCTGCCGCCTCCGTTTCCCGGTGCCG GGATTCCGAGGAAGAATGCACCGTAGGAGGGGCATGGCCG GCCACGGCCTGACGGGCGGCATGCGTCGTGCGCACCACCG GCGGCGGCGCGCGTCGCACCGTCGCATGCGCGGCGGTATC CTGCCCCTCCTTATTCCACTGATCGCCGCGGCGATTGGCGC CGTGCCCGGAATTGCATCCGTGGCCTTGCAGGCGCAGAGA CACTGATTAAAAACAAGTTGCATGTGGAAAAATCAAAATA AAAAGTCTGGACTCTCACGCTCGCTTGGTCCTGTAACTATT TTGTAGAATGGAAGACATCAACTTTGCGTCTCTGGCCCCGC GACACGGCTCGCGCCCGTTCATGGGAAACTGGCAAGATAT CGGCACCAGCAATATGAGCGGTGGCGCCTTCAGCTGGGGC TCGCTGTGGAGCGGCATTAAAAATTTCGGTTCCACCGTTAA GAACTATGGCAGCAAGGCCTGGAACAGCAGCACAGGCCA GATGCTGAGGGATAAGTTGAAAGAGCAAAATTTCCAACAA AAGGTGGTAGATGGCCTGGCCTCTGGCATTAGCGGGGTGG TGGACCTGGCCAACCAGGCAGTGCAAAATAAGATTAACAG TAAGCTTGATCCCCGCCCTCCCGTAGAGGAGCCTCCACCGG CCGTGGAGACAGTGTCTCCAGAGGGGCGTGGCGAAAAGCG TCCGCGCCCCGACAGGGAAGAAACTCTGGTGACGCAAATA GACGAGCCTCCCTCGTACGAGGAGGCACTAAAGCAAGGCC TGCCCACCACCCGTCCCATCGCGCCCATGGCTACCGGAGTG CTGGGCCAGCACACACCCGTAACGCTGGACCTGCCTCCCC CCGCCGACACCCAGCAGAAACCTGTGCTGCCAGGCCCGAC CGCCGTTGTTGTAACCCGTCCTAGCCGCGCGTCCCTGCGCC GCGCCGCCAGCGGTCCGCGATCGTTGCGGCCCGTAGCCAG TGGCAACTGGCAAAGCACACTGAACAGCATCGTGGGTCTG GGGGTGCAATCCCTGAAGCGCCGACGATGCTTCTGATAGC TAACGTGTCGTATGTGTGTCATGTATGCGTCCATGTCGCCG CCAGAGGAGCTGCTGAGCCGCCGCGCGCCCGCTTTCCAAG ATGGCTACCCCTTCGATGATGCCGCAGTGGTCTTACATGCA

CATCTCGGGCCAGGACGCCTCGGAGTACCTGAGCCCCGGG CTGGTGCAGTTTGCCCGCGCCACCGAGACGTACTTCAGCCT GAATAACAAGTTTAGAAACCCCACGGTGGCGCCTACGCAC GACGTGACCACAGACCGGTCCCAGCGTTTGACGCTGCGGT TCATCCCTGTGGACCGTGAGGATACTGCGTACTCGTACAAG GCGCGGTTCACCCTAGCTGTGGGTGATAACCGTGTGCTGG ACATGGCTTCCACGTACTTTGACATCCGCGGCGTGCTGGAC AGGGGCCCTACTTTTAAGCCCTACTCTGGCACTGCCTACAA CGCCCTGGCTCCCAAGGGTGCCCCAAATCCTTGCGAATGG GATGAAGCTGCTACTGCTCTTGAAATAAACCTAGAAGAAG AGGACGATGACAACGAAGACGAAGTAGACGAGCAAGCTG AGCAGCAAAAAACTCACGTATTTGGGCAGGCGCCTTATTC TGGTATAAATATTACAAAGGAGGGTATTCAAATAGGTGTC GAAGGTCAAACACCTAAATATGCCGATAAAACATTTCAAC CTGAACCTCAAATAGGAGAATCTCAGTGGTACGAAACAGA AATTAATCATGCAGCTGGGAGAGTCCTAAAAAAGACTACC CCAATGAAACCATGTTACGGTTCATATGCAAAACCCACAA ATGAAAATGGAGGGCAAGGCATTCTTGTAAAGCAACAAAA TGGAAAGCTAGAAAGTCAAGTGGAAATGCAATTTTTCTCA ACTACTGAGGCAGCCGCAGGCAATGGTGATAACTTGACTC CTAAAGTGGTATTGTACAGTGAAGATGTAGATATAGAAAC CCCAGACACTCATATTTCTTACATGCCCACTATTAAGGAAG GTAACTCACGAGAACTAATGGGCCAACAATCTATGCCCAA CAGGCCTAATTACATTGCTTTTAGGGACAATTTTATTGGTC TAATGTATTACAACAGCACGGGTAATATGGGTGTTCTGGC GGGCCAAGCATCGCAGTTGAATGCTGTTGTAGATTTGCAA GACAGAAACACAGAGCTTTCATACCAGCTTTTGCTTGATTC CATTGGTGATAGAACCAGGTACTTTTCTATGTGGAATCAGG CTGTTGACAGCTATGATCCAGATGTTAGAATTATTGAAAAT CATGGAACTGAAGATGAACTTCCAAATTACTGCTTTCCACT GGGAGGTGTGATTAATACAGAGACTCTTACCAAGGTAAAA CCTAAAACAGGTCAGGAAAATGGATGGGAAAAAGATGCT ACAGAATTTTCAGATAAAAATGAAATAAGAGTTGGAAATA ATTTTGCCATGGAAATCAATCTAAATGCCAACCTGTGGAG AAATTTCCTGTACTCCAACATAGCGCTGTATTTGCCCGACA AGCTAAAGTACAGTCCTTCCAACGTAAAAATTTCTGATAAC CCAAACACCTACGACTACATGAACAAGCGAGTGGTGGCTC CCGGGCTAGTGGACTGCTACATTAACCTTGGAGCACGCTG GTCCCTTGACTATATGGACAACGTCAACCCATTTAACCACC ACCGCAATGCTGGCCTGCGCTACCGCTCAATGTTGCTGGGC AATGGTCGCTATGTGCCCTTCCACATCCAGGTGCCTCAGAA GTTCTTTGCCATTAAAAACCTCCTTCTCCTGCCGGGCTCAT ACACCTACGAGTGGAACTTCAGGAAGGATGTTAACATGGT TCTGCAGAGCTCCCTAGGAAATGACCTAAGGGTTGACGGA GCCAGCATTAAGTTTGATAGCATTTGCCTTTACGCCACCTT CTTCCCCATGGCCCACAACACCGCCTCCACGCTTGAGGCCA TGCTTAGAAACGACACCAACGACCAGTCCTTTAACGACTA TCTCTCCGCCGCCAACATGCTCTACCCTATACCCGCCAACG CTACCAACGTGCCCATATCCATCCCCTCCCGCAACTGGGCG GCTTTCCGCGGCTGGGCCTTCACGCGCCTTAAGACTAAGGA AACCCCATCACTGGGCTCGGGCTACGACCCTTATTACACCT ACTCTGGCTCTATACCCTACCTAGATGGAACCTTTTACCTC AACCACACCTTTAAGAAGGTGGCCATTACCTTTGACTCTTC TGTCAGCTGGCCTGGCAATGACCGCCTGCTTACCCCCAACG AGTTTGAAATTAAGCGCTCAGTTGACGGGGAGGGTTACAA CGTTGCCCAGTGTAACATGACCAAAGACTGGTTCCTGGTAC AAATGCTAGCTAACTATAACATTGGCTACCAGGGCTTCTAT ATCCCAGAGAGCTACAAGGACCGCATGTACTCCTTCTTTAG AAACTTCCAGCCCATGAGCCGTCAGGTGGTGGATGATACT AAATACAAGGACTACCAACAGGTGGGCATCCTACACCAAC ACAACAACTCTGGATTTGTTGGCTACCTTGCCCCCACCATG CGCGAAGGACAGGCCTACCCTGCTAACTTCCCCTATCCGCT TATAGGCAAGACCGCAGTTGACAGCATTACCCAGAAAAAG TTTCTTTGCGATCGCACCCTTTGGCGCATCCCATTCTCCAGT AACTTTATGTCCATGGGCGCACTCACAGACCTGGGCCAAA ACCTTCTCTACGCCAACTCCGCCCACGCGCTAGACATGACT TTTGAGGTGGATCCCATGGACGAGCCCACCCTTCTTTATGT TTTGTTTGAAGTCTTTGACGTGGTCCGTGTGCACCAGCCGC ACCGCGGCGTCATCGAAACCGTGTACCTGCGCACGCCCTTC TCGGCCGGCAACGCCACAACATAAAGAAGCAAGCAACATC AACAACAGCTGCCGCCATGGGCTCCAGTGAGCAGGAACTG AAAGCCATTGTCAAAGATCTTGGTTGTGGGCCATATTTTTT GGGCACCTATGACAAGCGCTTTCCAGGCTTTGTTTCTCCAC ACAAGCTCGCCTGCGCCATAGTCAATACGGCCGGTCGCGA GACTGGGGGCGTACACTGGATGGCCTTTGCCTGGAACCCG CACTCAAAAACATGCTACCTCTTTGAGCCCTTTGGCTTTTC TGACCAGCGACTCAAGCAGGTTTACCAGTTTGAGTACGAG TCACTCCTGCGCCGTAGCGCCATTGCTTCTTCCCCCGACCG CTGTATAACGCTGGAAAAGTCCACCCAAAGCGTACAGGGG CCCAACTCGGCCGCCTGTGGACTATTCTGCTGCATGTTTCT CCACGCCTTTGCCAACTGGCCCCAAACTCCCATGGATCACA ACCCCACCATGAACCTTATTACCGGGGTACCCAACTCCATG CTCAACAGTCCCCAGGTACAGCCCACCCTGCGTCGCAACC AGGAACAGCTCTACAGCTTCCTGGAGCGCCACTCGCCCTA CTTCCGCAGCCACAGTGCGCAGATTAGGAGCGCCACTTCTT TTTGTCACTTGAAAAACATGTAAAAATAATGTACTAGAGA CACTTTCAATAAAGGCAAATGCTTTTATTTGTACACTCTCG GGTGATTATTTACCCCCACCCTTGCCGTCTGCGCCGTTTAA AAATCAAAGGGGTTCTGCCGCGCATCGCTATGCGCCACTG GCAGGGACACGTTGCGATACTGGTGTTTAGTGCTCCACTTA AACTCAGGCACAACCATCCGCGGCAGCTCGGTGAAGTTTT CACTCCACAGGCTGCGCACCATCACCAACGCGTTTAGCAG GTCGGGCGCCGATATCTTGAAGTCGCAGTTGGGGCCTCCG CCCTGCGCGCGCGAGTTGCGATACACAGGGTTGCAGCACT GGAACACTATCAGCGCCGGGTGGTGCACGCTGGCCAGCAC GCTCTTGTCGGAGATCAGATCCGCGTCCAGGTCCTCCGCGT TGCTCAGGGCGAACGGAGTCAACTTTGGTAGCTGCCTTCCC AAAAAGGGCGCGTGCCCAGGCTTTGAGTTGCACTCGCACC GTAGTGGCATCAAAAGGTGACCGTGCCCGGTCTGGGCGTT AGGATACAGCGCCTGCATAAAAGCCTTGATCTGCTTAAAA GCCACCTGAGCCTTTGCGCCTTCAGAGAAGAACATGCCGC AAGACTTGCCGGAAAACTGATTGGCCGGACAGGCCGCGTC GTGCACGCAGCACCTTGCGTCGGTGTTGGAGATCTGCACC ACATTTCGGCCCCACCGGTTCTTCACGATCTTGGCCTTGCT AGACTGCTCCTTCAGCGCGCGCTGCCCGTTTTCGCTCGTCA CATCCATTTCAATCACGTGCTCCTTATTTATCATAATGCTTC CGTGTAGACACTTAAGCTCGCCTTCGATCTCAGCGCAGCGG TGCAGCCACAACGCGCAGCCCGTGGGCTCGTGATGCTTGT AGGTCACCTCTGCAAACGACTGCAGGTACGCCTGCAGGAA TCGCCCCATCATCGTCACAAAGGTCTTGTTGCTGGTGAAGG TCAGCTGCAACCCGCGGTGCTCCTCGTTCAGCCAGGTCTTG CATACGGCCGCCAGAGCTTCCACTTGGTCAGGCAGTAGTTT GAAGTTCGCCTTTAGATCGTTATCCACGTGGTACTTGTCCA TCAGCGCGCGCGCAGCCTCCATGCCCTTCTCCCACGCAGAC ACGATCGGCACACTCAGCGGGTTCATCACCGTAATTTCACT TTCCGCTTCGCTGGGCTCTTCCTCTTCCTCTTGCGTCCGCAT ACCACGCGCCACTGGGTCGTCTTCATTCAGCCGCCGCACTG TGCGCTTACCTCCTTTGCCATGCTTGATTAGCACCGGTGGG TTGCTGAAACCCACCATTTGTAGCGCCACATCTTCTCTTTCT TCCTCGCTGTCCACGATTACCTCTGGTGATGGCGGGCGCTC GGGCTTGGGAGAAGGGCGCTTCTTTTTCTTCTTGGGCGCAA TGGCCAAATCCGCCGCCGAGGTCGATGGCCGCGGGCTGGG TGTGCGCGGCACCAGCGCGTCTTGTGATGAGTCTTCCTCGT CCTCGGACTCGATACGCCGCCTCATCCGCTTTTTTGGGGGC GCCCGGGGAGGCGGCGGCGACGGGGACGGGGACGACACG TCCTCCATGGTTGGGGGACGTCGCGCCGCACCGCGTCCGC GCTCGGGGGTGGTTTCGCGCTGCTCCTCTTCCCGACTGGCC ATTTCCTTCTCCTATAGGCAGAAAAAGATCATGGAGTCAGT CGAGAAGAAGGACAGCCTAACCGCCCCCTCTGAGTTCGCC ACCACCGCCTCCACCGATGCCGCCAACGCGCCTACCACCTT CCCCGTCGAGGCACCCCCGCTTGAGGAGGAGGAAGTGATT ATCGAGCAGGACCCAGGTTTTGTAAGCGAAGACGACGAGG ACCGCTCAGTACCAACAGAGGATAAAAAGCAAGACCAGG ACAACGCAGAGGCAAACGAGGAACAAGTCGGGCGGGGGG ACGAAAGGCATGGCGACTACCTAGATGTGGGAGACGACGT GCTGTTGAAGCATCTGCAGCGCCAGTGCGCCATTATCTGCG ACGCGTTGCAAGAGCGCAGCGATGTGCCCCTCGCCATAGC GGATGTCAGCCTTGCCTACGAACGCCACCTATTCTCACCGC GCGTACCCCCCAAACGCCAAGAAAACGGCACATGCGAGCC CAACCCGCGCCTCAACTTCTACCCCGTATTTGCCGTGCCAG AGGTGCTTGCCACCTATCACATCTTTTTCCAAAACTGCAAG ATACCCCTATCCTGCCGTGCCAACCGCAGCCGAGCGGACA AGCAGCTGGCCTTGCGGCAGGGCGCTGTCATACCTGATAT CGCCTCGCTCAACGAAGTGCCAAAAATCTTTGAGGGTCTTG GACGCGACGAGAAGCGCGCGGCAAACGCTCTGCAACAGG AAAACAGCGAAAATGAAAGTCACTCTGGAGTGTTGGTGGA ACTCGAGGGTGACAACGCGCGCCTAGCCGTACTAAAACGC AGCATCGAGGTCACCCACTTTGCCTACCCGGCACTTAACCT ACCCCCCAAGGTCATGAGCACAGTCATGAGTGAGCTGATC GTGCGCCGTGCGCAGCCCCTGGAGAGGGATGCAAATTTGC AAGAACAAACAGAGGAGGGCCTACCCGCAGTTGGCGACG AGCAGCTAGCGCGCTGGCTTCAAACGCGCGAGCCTGCCGA CTTGGAGGAGCGACGCAAACTAATGATGGCCGCAGTGCTC GTTACCGTGGAGCTTGAGTGCATGCAGCGGTTCTTTGCTGA CCCGGAGATGCAGCGCAAGCTAGAGGAAACATTGCACTAC ACCTTTCGACAGGGCTACGTACGCCAGGCCTGCAAGATCT CCAACGTGGAGCTCTGCAACCTGGTCTCCTACCTTGGAATT TTGCACGAAAACCGCCTTGGGCAAAACGTGCTTCATTCCAC GCTCAAGGGCGAGGCGCGCCGCGACTACGTCCGCGACTGC GTTTACTTATTTCTATGCTACACCTGGCAGACGGCCATGGG CGTTTGGCAGCAGTGCTTGGAGGAGTGCAACCTCAAGGAG CTGCAGAAACTGCTAAAGCAAAACTTGAAGGACCTATGGA CGGCCTTCAACGAGCGCTCCGTGGCCGCGCACCTGGCGGA CATCATTTTCCCCGAACGCCTGCTTAAAACCCTGCAACAGG GTCTGCCAGACTTCACCAGTCAAAGCATGTTGCAGAACTTT AGGAACTTTATCCTAGAGCGCTCAGGAATCTTGCCCGCCAC CTGCTGTGCACTTCCTAGCGACTTTGTGCCCATTAAGTACC GCGAATGCCCTCCGCCGCTTTGGGGCCACTGCTACCTTCTG CAGCTAGCCAACTACCTTGCCTACCACTCTGACATAATGGA AGACGTGAGCGGTGACGGTCTACTGGAGTGTCACTGTCGC TGCAACCTATGCACCCCGCACCGCTCCCTGGTTTGCAATTC GCAGCTGCTTAACGAAAGTCAAATTATCGGTACCTTTGAGC TGCAGGGTCCCTCGCCTGACGAAAAGTCCGCGGCTCCGGG GTTGAAACTCACTCCGGGGCTGTGGACGTCGGCTTACCTTC GCAAATTTGTACCTGAGGACTACCACGCCCACGAGATTAG GTTCTACGAAGACCAATCCCGCCCGCCTAATGCGGAGCTT ACCGCCTGCGTCATTACCCAGGGCCACATTCTTGGCCAATT GCAAGCCATCAACAAAGCCCGCCAAGAGTTTCTGCTACGA AAGGGACGGGGGGTTTACTTGGACCCCCAGTCCGGCGAGG AGCTCAACCCAATCCCCCCGCCGCCGCAGCCCTATCAGCA GCAGCCGCGGGCCCTTGCTTCCCAGGATGGCACCCAAAAA GAAGCTGCAGCTGCCGCCGCCACCCACGGACGAGGAGGAA TACTGGGACAGTCAGGCAGAGGAGGTTTTGGACGAGGAGG AGGAGGACATGATGGAAGACTGGGAGAGCCTAGACGAGG AAGCTTCCGAGGTCGAAGAGGTGTCAGACGAAACACCGTC ACCCTCGGTCGCATTCCCCTCGCCGGCGCCCCAGAAATCGG CAACCGGTTCCAGCATGGCTACAACCTCCGCTCCTCAGGCG CCGCCGGCACTGCCCGTTCGCCGACCCAACCGTAGATGGG ACACCACTGGAACCAGGGCCGGTAAGTCCAAGCAGCCGCC GCCGTTAGCCCAAGAGCAACAACAGCGCCAAGGCTACCGC TCATGGCGCGGGCACAAGAACGCCATAGTTGCTTGCTTGC AAGACTGTGGGGGCAACATCTCCTTCGCCCGCCGCTTTCTT CTCTACCATCACGGCGTGGCCTTCCCCCGTAACATCCTGCA TTACTACCGTCATCTCTACAGCCCATACTGCACCGGCGGCA GCGGCAGCAACAGCAGCGGCCACACAGAAGCAAAGGCGA CCGGATAGCAAGACTCTGACAAAGCCCAAGAAATCCACAG CGGCGGCAGCAGCAGGAGGAGGAGCGCTGCGTCTGGCGCC CAACGAACCCGTATCGACCCGCGAGCTTAGAAACAGGATT TTTCCCACTCTGTATGCTATATTTCAACAGAGCAGGGGCCA AGAACAAGAGCTGAAAATAAAAAACAGGTCTCTGCGATCC CTCACCCGCAGCTGCCTGTATCACAAAAGCGAAGATCAGC TTCGGCGCACGCTGGAAGACGCGGAGGCTCTCTTCAGTAA ATACTGCGCGCTGACTCTTAAGGACTAGTTTCGCGCCCTTT CTCAAATTTAAGCGCGAAAACTACGTCATCTCCAGCGGCC ACACCCGGCGCCAGCACCTGTTGTCAGCGCCATTATGAGC AAGGAAATTCCCACGCCCTACATGTGGAGTTACCAGCCAC AAATGGGACTTGCGGCTGGAGCTGCCCAAGACTACTCAAC CCGAATAAACTACATGAGCGCGGGACCCCACATGATATCC CGGGTCAACGGAATACGCGCCCACCGAAACCGAATTCTCC TGGAACAGGCGGCTATTACCACCACACCTCGTAATAACCTT AATCCCCGTAGTTGGCCCGCTGCCCTGGTGTACCAGGAAA GTCCCGCTCCCACCACTGTGGTACTTCCCAGAGACGCCCAG GCCGAAGTTCAGATGACTAACTCAGGGGCGCAGCTTGCGG GCGGCTTTCGTCACAGGGTGCGGTCGCCCGGGCAGGGTAT AACTCACCTGACAATCAGAGGGCGAGGTATTCAGCTCAAC GACGAGTCGGTGAGCTCCTCGCTTGGTCTCCGTCCGGACGG GACATTTCAGATCGGCGGCGCCGGCCGCTCTTCATTCACGC CTCGTCAGGCAATCCTAACTCTGCAGACCTCGTCCTCTGAG CCGCGCTCTGGAGGCATTGGAACTCTGCAATTTATTGAGGA GTTTGTGCCATCGGTCTACTTTAACCCCTTCTCGGGACCTC CCGGCCACTATCCGGATCAATTTATTCCTAACTTTGACGCG GTAAAGGACTCGGCGGACGGCTACGACTGAATGTTAAGTG GAGAGGCAGAGCAACTGCGCCTGAAACACCTGGTCCACTG TCGCCGCCACAAGTGCTTTGCCCGCGACTCCGGTGAGTTTT GCTACTTTGAATTGCCCGAGGATCATATCGAGGGCCCGGC GCACGGCGTCCGGCTTACCGCCCAGGGAGAGCTTGCCCGT AGCCTGATTCGGGAGTTTACCCAGCGCCCCCTGCTAGTTGA GCGGGACAGGGGACCCTGTGTTCTCACTGTGATTTGCAACT GTCCTAACCCTGGATTACATCAAGATCCTCTAGTTAATGTC AGGTCGCCTAAGTCGATTAACTAGAGTACCCGGGGATCTT ATTCCCTTTAACTAATAAAAAAAAATAATAAAGCATCACTT ACTTAAAATCAGTTAGCAAATTTCTGTCCAGTTTATTCAGC AGCACCTCCTTGCCCTCCTCCCAGCTCTGGTATTGCAGCTT CCTCCTGGCTGCAAACTTTCTCCACAATCTAAATGGAATGT CAGTTTCCTCCTGTTCCTGTCCATCCGCACCCACTATCTTCA TGTTGTTGCAGATGAAGCGCGCAAGACCGTCTGAAGATAC CTTCAACCCCGTGTATCCATATGACACGGAAACCGGTCCTC CAACTGTGCCTTTTCTTACTCCTCCCTTTGTATCCCCCAATG GGTTTCAAGAGAGTCCCCCTGGGGTACTCTCTTTGCGCCTA TCCGAACCTCTAGTTACCTCCAATGGCATGCTTGCGCTCAA AATGGGCAACGGCCTCTCTCTGGACGAGGCCGGCAACCTT ACCTCCCAAAATGTAACCACTGTGAGCCCACCTCTCAAAA AAACCAAGTCAAACATAAACCTGGAAATATCTGCACCCCT CACAGTTACCTCAGAAGCCCTAACTGTGGCTGCCGCCGCA CCTCTAATGGTCGCGGGCAACACACTCACCATGCAATCAC AGGCCCCGCTAACCGTGCACGACTCCAAACTTAGCATTGC CACCCAAGGACCCCTCACAGTGTCAGAAGGAAAGCTAGCC CTGCAAACATCAGGCCCCCTCACCACCACCGATAGCAGTA CCCTTACTATCACTGCCTCACCCCCTCTAACTACTGCCACT GGTAGCTTGGGCATTGACTTGAAAGAGCCCATTTATACAC AAAATGGAAAACTAGGACTAAAGTACGGGGCTCCTTTGCA

TGTAACAGACGACCTAAACACTTTGACCGTAGCAACTGGT CCAGGTGTGACTATTAATAATACTTCCTTGCAAACTAAAGT TACTGGAGCCTTGGGTTTTGATTCACAAGGCAATATGCAAC TTAATGTAGCAGGAGGACTAAGGATTGATTCTCAAAACAG ACGCCTTATACTTGATGTTAGTTATCCGTTTGATGCTCAAA ACCAACTAAATCTAAGACTAGGACAGGGCCCTCTTTTTATA AACTCAGCCCACAACTTGGATATTAACTACAACAAAGGCC TTTACTTGTTTACAGCTTCAAACAATTCCAAAAAGCTTGAG GTTAACCTAAGCACTGCCAAGGGGTTGATGTTTGACGCTAC AGCCATAGCCATTAATGCAGGAGATGGGCTTGAATTTGGT TCACCTAATGCACCAAACACAAATCCCCTCAAAACAAAAA TTGGCCATGGCCTAGAATTTGATTCAAACAAGGCTATGGTT CCTAAACTAGGAACTGGCCTTAGTTTTGACAGCACAGGTG CCATTACAGTAGGAAACAAAAATAATGATAAGCTAACTTT GTGGACCACACCAGCTCCATCTCCTAACTGTAGACTAAATG CAGAGAAAGATGCTAAACTCACTTTGGTCTTAACAAAATG TGGCAGTCAAATACTTGCTACAGTTTCAGTTTTGGCTGTTA AAGGCAGTTTGGCTCCAATATCTGGAACAGTTCAAAGTGC TCATCTTATTATAAGATTTGACGAAAATGGAGTGCTACTAA ACAATTCCTTCCTGGACCCAGAATATTGGAACTTTAGAAAT GGAGATCTTACTGAAGGCACAGCCTATACAAACGCTGTTG GATTTATGCCTAACCTATCAGCTTATCCAAAATCTCACGGT AAAACTGCCAAAAGTAACATTGTCAGTCAAGTTTACTTAA ACGGAGACAAAACTAAACCTGTAACACTAACCATTACACT AAACGGTACACAGGAAACAGGAGACACAACTCCAAGTGC ATACTCTATGTCATTTTCATGGGACTGGTCTGGCCACAACT ACATTAATGAAATATTTGCCACATCCTCTTACACTTTTTCAT ACATTGCCCAAGAATAAAGAATCGTTTGTGTTATGTTTCAA CGTGTTTATTTTTCAATTGCAGAAAATTTCAAGTCATTTTTC ATTCAGTAGTATAGCCCCACCACCACATAGCTTATACAGAT CACCGTACCTTAATCAAACTCACAGAACCCTAGTATTCAAC CTGCCACCTCCCTCCCAACACACAGAGTACACAGTCCTTTC TCCCCGGCTGGCCTTAAAAAGCATCATATCATGGGTAACA GACATATTCTTAGGTGTTATATTCCACACGGTTTCCTGTCG AGCCAAACGCTCATCAGTGATATTAATAAACTCCCCGGGC AGCTCACTTAAGTTCATGTCGCTGTCCAGCTGCTGAGCCAC AGGCTGCTGTCCAACTTGCGGTTGCTTAACGGGCGGCGAA GGAGAAGTCCACGCCTACATGGGGGTAGAGTCATAATCGT GCATCAGGATAGGGCGGTGGTGCTGCAGCAGCGCGCGAAT AAACTGCTGCCGCCGCCGCTCCGTCCTGCAGGAATACAAC ATGGCAGTGGTCTCCTCAGCGATGATTCGCACCGCCCGCA GCATAAGGCGCCTTGTCCTCCGGGCACAGCAGCGCACCCT GATCTCACTTAAATCAGCACAGTAACTGCAGCACAGCACC ACAATATTGTTCAAAATCCCACAGTGCAAGGCGCTGTATCC AAAGCTCATGGCGGGGACCACAGAACCCACGTGGCCATCA TACCACAAGCGCAGGTAGATTAAGTGGCGACCCCTCATAA ACACGCTGGACATAAACATTACCTCTTTTGGCATGTTGTAA TTCACCACCTCCCGGTACCATATAAACCTCTGATTAAACAT GGCGCCATCCACCACCATCCTAAACCAGCTGGCCAAAACC TGCCCGCCGGCTATACACTGCAGGGAACCGGGACTGGAAC AATGACAGTGGAGAGCCCAGGACTCGTAACCATGGATCAT CATGCTCGTCATGATATCAATGTTGGCACAACACAGGCAC ACGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGT TAGAACCATATCCCAGGGAACAACCCATTCCTGAATCAGC GTAAATCCCACACTGCAGGGAAGACCTCGCACGTAACTCA CGTTGTGCATTGTCAAAGTGTTACATTCGGGCAGCAGCGG ATGATCCTCCAGTATGGTAGCGCGGGTTTCTGTCTCAAAAG GAGGTAGACGATCCCTACTGTACGGAGTGCGCCGAGACAA CCGAGATCGTGTTGGTCGTAGTGTCATGCCAAATGGAACG CCGGACGTAGTCATATTTCCTGAAGCAAAACCAGGTGCGG GCGTGACAAACAGATCTGCGTCTCCGGTCTCGCCGCTTAGA TCGCTCTGTGTAGTAGTTGTAGTATATCCACTCTCTCAAAG CATCCAGGCGCCCCCTGGCTTCGGGTTCTATGTAAACTCCT TCATGCGCCGCTGCCCTGATAACATCCACCACCGCAGAAT AAGCCACACCCAGCCAACCTACACATTCGTTCTGCGAGTC ACACACGGGAGGAGCGGGAAGAGCTGGAAGAACCATGTT TTTTTTTTTATTCCAAAAGATTATCCAAAACCTCAAAATGA AGATCTATTAAGTGAACGCGCTCCCCTCCGGTGGCGTGGTC AAACTCTACAGCCAAAGAACAGATAATGGCATTTGTAAGA TGTTGCACAATGGCTTCCAAAAGGCAAACGGCCCTCACGT CCAAGTGGACGTAAAGGCTAAACCCTTCAGGGTGAATCTC CTCTATAAACATTCCAGCACCTTCAACCATGCCCAAATAAT TCTCATCTCGCCACCTTCTCAATATATCTCTAAGCAAATCC CGAATATTAAGTCCGGCCATTGTAAAAATCTGCTCCAGAG CGCCCTCCACCTTCAGCCTCAAGCAGCGAATCATGATTGCA AAAATTCAGGTTCCTCACAGACCTGTATAAGATTCAAAAG CGGAACATTAACAAAAATACCGCGATCCCGTAGGTCCCTT CGCAGGGCCAGCTGAACATAATCGTGCAGGTCTGCACGGA CCAGCGCGGCCACTTCCCCGCCAGGAACCATGACAAAAGA ACCCACACTGATTATGACACGCATACTCGGAGCTATGCTA ACCAGCGTAGCCCCGATGTAAGCTTGTTGCATGGGCGGCG ATATAAAATGCAAGGTGCTGCTCAAAAAATCAGGCAAAGC CTCGCGCAAAAAAGAAAGCACATCGTAGTCATGCTCATGC AGATAAAGGCAGGTAAGCTCCGGAACCACCACAGAAAAA GACACCATTTTTCTCTCAAACATGTCTGCGGGTTTCTGCAT AAACACAAAATAAAATAACAAAAAAACATTTAAACATTAG AAGCCTGTCTTACAACAGGAAAAACAACCCTTATAAGCAT AAGACGGACTACGGCCATGCCGGCGTGACCGTAAAAAAAC TGGTCACCGTGATTAAAAAGCACCACCGACAGCTCCTCGG TCATGTCCGGAGTCATAATGTAAGACTCGGTAAACACATC AGGTTGATTCACATCGGTCAGTGCTAAAAAGCGACCGAAA TAGCCCGGGGGAATACATACCCGCAGGCGTAGAGACAACA TTACAGCCCCCATAGGAGGTATAACAAAATTAATAGGAGA GAAAAACACATAAACACCTGAAAAACCCTCCTGCCTAGGC AAAATAGCACCCTCCCGCTCCAGAACAACATACAGCGCTT CCACAGCGGCAGCCATAACAGTCAGCCTTACCAGTAAAAA AGAAAACCTATTAAAAAAACACCACTCGACACGGCACCAG CTCAATCAGTCACAGTGTAAAAAAGGGCCAAGTGCAGAGC GAGTATATATAGGACTAAAAAATGACGTAACGGTTAAAGT CCACAAAAAACACCCAGAAAACCGCACGCGAACCTACGCC CAGAAACGAAAGCCAAAAAACCCACAACTTCCTCAAATCG TCACTTCCGTTTTCCCACGTTACGTCACTTCCCATTTTAAGA AAACTACAATTCCCAACACATACAAGTTACTCCGCCCTAA AACCTACGTCACCCGCCCCGTTCCCACGCCCCGCGCCACGT CACAAACTCCACCCCCTCATTATCATATTGGCTTCAATCCA AAATAAGGTATATTATTGATGATG 95 Full nucleotide (human IL- TTTTGGATTGAAGCCAATATGATAATGAGGGGGTGGAGTT sequence of 12 insert TGTGACGTGGCGCGGGGCGTGGGAACGGGGCGGGTGACGT TRZ627 hIL- sequence in AGTAGTGTGGCGGAAGTGTGATGTTGCAAGTGTGGCGGAA 12 virus CACATGTAAGCGACGGATGTGGCAAAAGTGACGTTTTTGG bold codon TGTGCGCCGGTGTTTTGGGCGTAACCGAGTAAGATTTGGCC (beginning at ATTTTCGCGGGAAAACTGAATAAGAGGAAGTGAAATCTGA optimized) ATAATTTTGTGTTACTCATAGCGCGTAATATTTGTCTAGGG Ad5 5' end CCGCGGGGACTTTGACCGTTTACGTGGAGACTCGCCCAGG ITR) TGTTTTTCTCAGGTGTTTTCCGCGTTCCGGGTCAAAGTTGG CGTTTTATTATTATAGTCAGCTGACGTGTAGTGTATTTATA CCCGGTGAGTTCCTCAAGAGGCCACTCTTGAGTGCCAGCG AGTAGAGTTTTCTCCTCCGAGCCGCTCCGACACCGGGACTG AAAATGAGACATATTATCTGCCACGGAGGTGTTATTACCG AAGAAATGGCCGCCAGTCTTTTGGACCAGCTGATCGAAGA GGTACTGGCTGATAATCTTCCACCTCCTAGCCATTTTGAAC CACCTACCCTTCACGAACTGTATGATTTAGACGTGACGGCC CCCGAAGATCCCAACGAGGAGGCGGTTTCGCAGATTTTTC CCGACTCTGTAATGTTGGCGGTGCAGGAAGGGATTGACTT ACTCACTTTTCCGCCGGCGCCCGGTTCTCCGGAGCCGCCTC ACCTTTCCCGGCAGCCCGAGCAGCCGGAGCAGAGAGCCTT GGGTCCGGTTTCTATGCCAAACCTTGTACCGGAGGTGATCG ATCTTACCTGCCACGAGGCTGGCTTTCCACCCAGTGACGAC GAGGATGAAGAGGGTGAGGAGTTTGTGTTAGATTATGTGG AGCACCCCGGGCACGGTTGCAGGTCTTGTCATTATCACCGG AGGAATACGGGGGACCCAGATATTATGTGTTCGCTTTGCTA TATGAGGACCTGTGGCATGTTTGTCTACAGTAAGTGAAAAT TATGGGCAGTGGGTGATAGAGTGGTGGGTTTGGTGTGGTA ATTTTTTTTTTAATTTTTACAGTTTTGTGGTTTAAAGAATTT TGTATTGTGATTTTTTTAAAAGGTCCTGTGTCTGAACCTGA GCCTGAGCCCGAGCCAGAACCGGAGCCTGCAAGACCTACC CGCCGTCCTAAAATGGCGCCTGCTATCCTGAGACGCCCGA CATCACCTGTGTCTAGAGAATGCAATAGTAGTACGGATAG CTGTGACTCCGGTCCTTCTAACACACCTCCTGAGATACACC CGGTGGTCCCGCTGTGCCCCATTAAACCAGTTGCCGTGAGA GTTGGTGGGCGTCGCCAGGCTGTGGAATGTATCGAGGACT TGCTTAACGAGCCTGGGCAACCTTTGGACTTGAGCTGTAAA CGCCCCAGGCCATAAGGTGTAAACCTGTGATTGCGTGTGT GGTTAACGCCTTTGTTTGCTGAATGAGTTGATGTAAGTTTA ATAAAGGGTGAGATAATGTTTAACTTGCATGGCGTGTTAA ATGGGGCGGGGCTTAAAGGGTATATAATGCGCCGTGGGCT AATCTTGGTTACATCTGACCTCGTCGACGCCACCATGTGT CACCAGCAGCTCGTGATTAGCTGGTTCAGCCTGGTGTT TCTGGCTAGCCCTCTGGTGGCCATCTGGGAGCTGAAGA AGGACGTGTACGTGGTGGAGCTCGACTGGTACCCTGAC GCTCCCGGCGAGATGGTCGTGCTGACCTGCGACACCCC TGAGGAAGATGGCATCACCTGGACCCTGGATCAAAGCT CCGAAGTGCTCGGCAGCGGCAAGACACTCACCATCCAG GTGAAAGAGTTCGGAGACGCCGGCCAGTACACCTGCCA CAAAGGCGGCGAGGTGCTGTCCCATTCCCTGCTGCTGC TGCACAAGAAAGAGGATGGCATCTGGTCCACCGACATC CTGAAGGACCAGAAGGAACCCAAGAACAAGACCTTTCT GAGATGTGAGGCCAAGAACTACAGCGGCAGGTTCACCT GCTGGTGGCTGACAACAATCTCCACCGACCTGACCTTC AGCGTCAAGAGCAGCAGGGGCAGCAGCGACCCTCAAG GCGTGACATGTGGAGCCGCTACCCTGAGCGCTGAGAGA GTCAGGGGCGACAATAAGGAGTACGAGTACTCCGTGGA ATGCCAGGAGGACTCCGCCTGCCCTGCCGCCGAAGAGT CCCTCCCTATCGAAGTGATGGTTGATGCCGTGCACAAG CTCAAGTATGAGAATTACACCAGCAGCTTTTTCATCAG GGACATCATCAAGCCCGACCCCCCCAAAAACCTCCAGC TGAAACCCCTCAAGAATAGCAGGCAGGTGGAGGTCTCC TGGGAGTATCCTGACACCTGGAGCACCCCCCACAGCTA CTTCTCCCTGACCTTCTGTGTGCAGGTGCAGGGCAAGA GCAAAAGGGAGAAGAAGGATAGGGTCTTTACCGACAAG ACCAGCGCCACAGTGATCTGCAGGAAGAACGCCAGCAT TTCCGTCAGGGCCCAGGACAGGTACTACAGCAGCAGCT GGTCCGAGTGGGCTAGCGTGCCTTGTTCCGGCGGCGG AGGATCTGGCGGAGGCGGAAGTGGCGGAGGGGGCTCT AGAAACCTCCCCGTGGCCACACCCGACCCTGGCATGTT CCCCTGCCTCCACCACAGCCAGAACCTGCTGAGAGCCG TGAGCAATATGCTGCAGAAGGCCAGGCAAACCCTGGAG TTCTACCCCTGTACCTCCGAGGAGATTGACCATGAGGA CATCACAAAGGACAAAACCAGCACCGTGGAGGCCTGTC TCCCCCTCGAACTGACCAAGAACGAGTCCTGCCTGAAC TCCAGGGAGACATCCTTCATCACCAACGGCTCCTGCCT GGCCTCCAGAAAGACCAGCTTCATGATGGCCCTCTGCC TGAGCAGCATCTACGAGGACCTCAAGATGTACCAGGTG GAGTTTAAAACAATGAACGCCAAGCTCCTCATGGACCC TAAGAGGCAGATTTTCCTCGACCAGAATATGCTGGCTG TCATTGACGAGCTGATGCAGGCCCTCAATTTCAACTCC GAGACCGTCCCCCAGAAGTCCTCCCTGGAAGAGCCCGA CTTTTACAAGACCAAGATCAAGCTCTGCATCCTGCTGC ACGCCTTCAGAATTAGAGCCGTGACCATTGACAGGGTG ATGAGCTACCTCAACGCCTCCTGATGACTCGAGTCACCA GGCGCTTTTCCAAGAGAAGGTCATCAAGACTTTGGATTTTT CCACACCGGGGCGCGCTGCGGCTGCTGTTGCTTTTTTGAGT TTTATAAAGGATAAATGGAGCGAAGAAACCCATCTGAGCG GGGGGTACCTGCTGGATTTTCTGGCCATGCATCTGTGGAGA GCGGTTGTGAGACACAAGAATCGCCTGCTACTGTTGTCTTC CGTCCGCCCGGCGATAATACCGACGGAGGAGCAGCAGCAG CAGCAGGAGGAAGCCAGGCGGCGGCGGCAGGAGCAGAGC CCATGGAACCCGAGAGCCGGCCTGGACCCTCGGGAATGAA TGTTGTACAGGTGGCTGAACTGTATCCAGAACTGAGACGC ATTTTGACAATTACAGAGGATGGGCAGGGGCTAAAGGGGG TAAAGAGGGAGCGGGGGGCTTGTGAGGCTACAGAGGAGG CTAGGAATCTAGCTTTTAGCTTAATGACCAGACACCGTCCT GAGTGTATTACTTTTCAACAGATCAAGGATAATTGCGCTAA TGAGCTTGATCTGCTGGCGCAGAAGTATTCCATAGAGCAG CTGACCACTTACTGGCTGCAGCCAGGGGATGATTTTGAGG AGGCTATTAGGGTATATGCAAAGGTGGCACTTAGGCCAGA TTGCAAGTACAAGATCAGCAAACTTGTAAATATCAGGAAT TGTTGCTACATTTCTGGGAACGGGGCCGAGGTGGAGATAG ATACGGAGGATAGGGTGGCCTTTAGATGTAGCATGATAAA TATGTGGCCGGGGGTGCTTGGCATGGACGGGGTGGTTATT ATGAATGTAAGGTTTACTGGCCCCAATTTTAGCGGTACGGT TTTCCTGGCCAATACCAACCTTATCCTACACGGTGTAAGCT TCTATGGGTTTAACAATACCTGTGTGGAAGCCTGGACCGAT GTAAGGGTTCGGGGCTGTGCCTTTTACTGCTGCTGGAAGGG GGTGGTGTGTCGCCCCAAAAGCAGGGCTTCAATTAAGAAA TGCCTCTTTGAAAGGTGTACCTTGGGTATCCTGTCTGAGGG TAACTCCAGGGTGCGCCACAATGTGGCCTCCGACTGTGGTT GCTTCATGCTAGTGAAAAGCGTGGCTGTGATTAAGCATAA CATGGTATGTGGCAACTGCGAGGACAGGGCCTCTCAGATG CTGACCTGCTCGGACGGCAACTGTCACCTGCTGAAGACCA TTCACGTAGCCAGCCACTCTCGCAAGGCCTGGCCAGTGTTT GAGCATAACATACTGACCCGCTGTTCCTTGCATTTGGGTAA CAGGAGGGGGGTGTTCCTACCTTACCAATGCAATTTGAGTC ACACTAAGATATTGCTTGAGCCCGAGAGCATGTCCAAGGT GAACCTGAACGGGGTGTTTGACATGACCATGAAGATCTGG AAGGTGCTGAGGTACGATGAGACCCGCACCAGGTGCAGAC CCTGCGAGTGTGGCGGTAAACATATTAGGAACCAGCCTGT GATGCTGGATGTGACCGAGGAGCTGAGGCCCGATCACTTG GTGCTGGCCTGCACCCGCGCTGAGTTTGGCTCTAGCGATGA AGATACAGATTGAGGTACTGAAATGTGTGGGCGTGGCTTA AGGGTGGGAAAGAATATATAAGGTGGGGGTCTTATGTAGT TTTGTATCTGTTTTGCAGCAGCCGCCGCCGCCATGAGCACC AACTCGTTTGATGGAAGCATTGTGAGCTCATATTTGACAAC GCGCATGCCCCCATGGGCCGGGGTGCGTCAGAATGTGATG GGCTCCAGCATTGATGGTCGCCCCGTCCTGCCCGCAAACTC TACTACCTTGACCTACGAGACCGTGTCTGGAACGCCGTTGG AGACTGCAGCCTCCGCCGCCGCTTCAGCCGCTGCAGCCAC CGCCCGCGGGATTGTGACTGACTTTGCTTTCCTGAGCCCGC TTGCAAGCAGTGCAGCTTCCCGTTCATCCGCCCGCGATGAC AAGTTGACGGCTCTTTTGGCACAATTGGATTCTTTGACCCG GGAACTTAATGTCGTTTCTCAGCAGCTGTTGGATCTGCGCC AGCAGGTTTCTGCCCTGAAGGCTTCCTCCCCTCCCAATGCG GTTTAAAACATAAATAAAAAACCAGACTCTGTTTGGATTTG GATCAAGCAAGTGTCTTGCTGTCTTTATTTAGGGGTTTTGC GCGCGCGGTAGGCCCGGGACCAGCGGTCTCGGTCGTTGAG GGTCCTGTGTATTTTTTCCAGGACGTGGTAAAGGTGACTCT GGATGTTCAGATACATGGGCATAAGCCCGTCTCTGGGGTG GAGGTAGCACCACTGCAGAGCTTCATGCTGCGGGGTGGTG TTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCGTGGT GCCTAAAAATGTCTTTCAGTAGCAAGCTGATTGCCAGGGG

CAGGCCCTTGGTGTAAGTGTTTACAAAGCGGTTAAGCTGG GATGGGTGCATACGTGGGGATATGAGATGCATCTTGGACT GTATTTTTAGGTTGGCTATGTTCCCAGCCATATCCCTCCGG GGATTCATGTTGTGCAGAACCACCAGCACAGTGTATCCGG TGCACTTGGGAAATTTGTCATGTAGCTTAGAAGGAAATGC GTGGAAGAACTTGGAGACGCCCTTGTGACCTCCAAGATTTT CCATGCATTCGTCCATAATGATGGCAATGGGCCCACGGGC GGCGGCCTGGGCGAAGATATTTCTGGGATCACTAACGTCA TAGTTGTGTTCCAGGATGAGATCGTCATAGGCCATTTTTAC AAAGCGCGGGCGGAGGGTGCCAGACTGCGGTATAATGGTT CCATCCGGCCCAGGGGCGTAGTTACCCTCACAGATTTGCAT TTCCCACGCTTTGAGTTCAGATGGGGGGATCATGTCTACCT GCGGGGCGATGAAGAAAACGGTTTCCGGGGTAGGGGAGA TCAGCTGGGAAGAAAGCAGGTTCCTGAGCAGCTGCGACTT ACCGCAGCCGGTGGGCCCGTAAATCACACCTATTACCGGC TGCAACTGGTAGTTAAGAGAGCTGCAGCTGCCGTCATCCCT GAGCAGGGGGGCCACTTCGTTAAGCATGTCCCTGACTCGC ATGTTTTCCCTGACCAAATCCGCCAGAAGGCGCTCGCCGCC CAGCGATAGCAGTTCTTGCAAGGAAGCAAAGTTTTTCAAC GGTTTGAGACCGTCCGCCGTAGGCATGCTTTTGAGCGTTTG ACCAAGCAGTTCCAGGCGGTCCCACAGCTCGGTCACCTGC TCTACGGCATCTCGATCCAGCATATCTCCTCGTTTCGCGGG TTGGGGCGGCTTTCGCTGTACGGCAGTAGTCGGTGCTCGTC CAGACGGGCCAGGGTCATGTCTTTCCACGGGCGCAGGGTC CTCGTCAGCGTAGTCTGGGTCACGGTGAAGGGGTGCGCTC CGGGCTGCGCGCTGGCCAGGGTGCGCTTGAGGCTGGTCCT GCTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGG CCAGGTAGCATTTGACCATGGTGTCATAGTCCAGCCCCTCC GCGGCGTGGCCCTTGGCGCGCAGCTTGCCCTTGGAGGAGG CGCCGCACGAGGGGCAGTGCAGACTTTTGAGGGCGTAGAG CTTGGGCGCGAGAAATACCGATTCCGGGGAGTAGGCATCC GCGCCGCAGGCCCCGCAGACGGTCTCGCATTCCACGAGCC AGGTGAGCTCTGGCCGTTCGGGGTCAAAAACCAGGTTTCC CCCATGCTTTTTGATGCGTTTCTTACCTCTGGTTTCCATGAG CCGGTGTCCACGCTCGGTGACGAAAAGGCTGTCCGTGTCC CCGTATACAGACTTGAGAGGCCTGTCCTCGAGCGGTGTTCC GCGGTCCTCCTCGTATAGAAACTCGGACCACTCTGAGACA AAGGCTCGCGTCCAGGCCAGCACGAAGGAGGCTAAGTGGG AGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACTCGCTC CAGGGTGTGAAGACACATGTCGCCCTCTTCGGCATCAAGG AAGGTGATTGGTTTGTAGGTGTAGGCCACGTGACCGGGTG TTCCTGAAGGGGGGCTATAAAAGGGGGTGGGGGCGCGTTC GTCCTCACTCTCTTCCGCATCGCTGTCTGCGAGGGCCAGCT GTTGGGGTGAGTACTCCCTCTGAAAAGCGGGCATGACTTCT GCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGA TATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCA TCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTT GGTGGCAAACGACCCGTAGAGGGCGTTGGACAGCAACTTG GCGATGGAGCGCAGGGTTTGGTTTTTGTCGCGATCGGCGC GCTCCTTGGCCGCGATGTTTAGCTGCACGTATTCGCGCGCA ACGCACCGCCATTCGGGAAAGACGGTGGTGCGCTCGTCGG GCACCAGGTGCACGCGCCAACCGCGGTTGTGCAGGGTGAC AAGGTCAACGCTGGTGGCTACCTCTCCGCGTAGGCGCTCGT TGGTCCAGCAGAGGCGGCCGCCCTTGCGCGAGCAGAATGG CGGTAGGGGGTCTAGCTGCGTCTCGTCCGGGGGGTCTGCG TCCACGGTAAAGACCCCGGGCAGCAGGCGCGCGTCGAAGT AGTCTATCTTGCATCCTTGCAAGTCTAGCGCCTGCTGCCAT GCGCGGGCGGCAAGCGCGCGCTCGTATGGGTTGAGTGGGG GACCCCATGGCATGGGGTGGGTGAGCGCGGAGGCGTACAT GCCGCAAATGTCGTAAACGTAGAGGGGCTCTCTGAGTATT CCAAGATATGTAGGGTAGCATCTTCCACCGCGGATGCTGG CGCGCACGTAATCGTATAGTTCGTGCGAGGGAGCGAGGAG GTCGGGACCGAGGTTGCTACGGGCGGGCTGCTCTGCTCGG AAGACTATCTGCCTGAAGATGGCATGTGAGTTGGATGATA TGGTTGGACGCTGGAAGACGTTGAAGCTGGCGTCTGTGAG ACCTACCGCGTCACGCACGAAGGAGGCGTAGGAGTCGCGC AGCTTGTTGACCAGCTCGGCGGTGACCTGCACGTCTAGGG CGCAGTAGTCCAGGGTTTCCTTGATGATGTCATACTTATCC TGTCCCTTTTTTTTCCACAGCTCGCGGTTGAGGACAAACTC TTCGCGGTCTTTCCAGTACTCTTGGATCGGAAACCCGTCGG CCTCCGAACGGTAAGAGCCTAGCATGTAGAACTGGTTGAC GGCCTGGTAGGCGCAGCATCCCTTTTCTACGGGTAGCGCGT ATGCCTGCGCGGCCTTCCGGAGCGAGGTGTGGGTGAGCGC AAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTATTTGA AGTCAGTGTCGTCGCATCCGCCCTGCTCCCAGAGCAAAAA GTCCGTGCGCTTTTTGGAACGCGGATTTGGCAGGGCGAAG GTGACATCGTTGAAGAGTATCTTTCCCGCGCGAGGCATAA AGTTGCGTGTGATGCGGAAGGGTCCCGGCACCTCGGAACG GTTGTTAATTACCTGGGCGGCGAGCACGATCTCGTCAAAG CCGTTGATGTTGTGGCCCACAATGTAAAGTTCCAAGAAGC GCGGGATGCCCTTGATGGAAGGCAATTTTTTAAGTTCCTCG TAGGTGAGCTCTTCAGGGGAGCTGAGCCCGTGCTCTGAAA GGGCCCAGTCTGCAAGATGAGGGTTGGAAGCGACGAATGA GCTCCACAGGTCACGGGCCATTAGCATTTGCAGGTGGTCG CGAAAGGTCCTAAACTGGCGACCTATGGCCATTTTTTCTGG GGTGATGCAGTAGAAGGTAAGCGGGTCTTGTTCCCAGCGG TCCCATCCAAGGTTCGCGGCTAGGTCTCGCGCGGCAGTCAC TAGAGGCTCATCTCCGCCGAACTTCATGACCAGCATGAAG GGCACGAGCTGCTTCCCAAAGGCCCCCATCCAAGTATAGG TCTCTACATCGTAGGTGACAAAGAGACGCTCGGTGCGAGG ATGCGAGCCGATCGGGAAGAACTGGATCTCCCGCCACCAA TTGGAGGAGTGGCTATTGATGTGGTGAAAGTAGAAGTCCC TGCGACGGGCCGAACACTCGTGCTGGCTTTTGTAAAAACG TGCGCAGTACTGGCAGCGGTGCACGGGCTGTACATCCTGC ACGAGGTTGACCTGACGACCGCGCACAAGGAAGCAGAGTG GGAATTTGAGCCCCTCGCCTGGCGGGTTTGGCTGGTGGTCT TCTACTTCGGCTGCTTGTCCTTGACCGTCTGGCTGCTCGAG GGGAGTTACGGTGGATCGGACCACCACGCCGCGCGAGCCC AAAGTCCAGATGTCCGCGCGCGGCGGTCGGAGCTTGATGA CAACATCGCGCAGATGGGAGCTGTCCATGGTCTGGAGCTC CCGCGGCGTCAGGTCAGGCGGGAGCTCCTGCAGGTTTACC TCGCATAGACGGGTCAGGGCGCGGGCTAGATCCAGGTGAT ACCTAATTTCCAGGGGCTGGTTGGTGGCGGCGTCGATGGCT TGCAAGAGGCCGCATCCCCGCGGCGCGACTACGGTACCGC GCGGCGGGCGGTGGGCCGCGGGGGTGTCCTTGGATGATGC ATCTAAAAGCGGTGACGCGGGCGAGCCCCCGGAGGTAGGG GGGGCTCCGGACCCGCCGGGAGAGGGGGCAGGGGCACGT CGGCGCCGCGCGCGGGCAGGAGCTGGTGCTGCGCGCGTAG GTTGCTGGCGAACGCGACGACGCGGCGGTTGATCTCCTGA ATCTGGCGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCT TGAACCTGAAAGAGAGTTCGACAGAATCAATTTCGGTGTC GTTGACGGCGGCCTGGCGCAAAATCTCCTGCACGTCTCCTG AGTTGTCTTGATAGGCGATCTCGGCCATGAACTGCTCGATC TCTTCCTCCTGGAGATCTCCGCGTCCGGCTCGCTCCACGGT GGCGGCGAGGTCGTTGGAAATGCGGGCCATGAGCTGCGAG AAGGCGTTGAGGCCTCCCTCGTTCCAGACGCGGCTGTAGA CCACGCCCCCTTCGGCATCGCGGGCGCGCATGACCACCTG CGCGAGATTGAGCTCCACGTGCCGGGCGAAGACGGCGTAG TTTCGCAGGCGCTGAAAGAGGTAGTTGAGGGTGGTGGCGG TGTGTTCTGCCACGAAGAAGTACATAACCCAGCGTCGCAA CGTGGATTCGTTGATATCCCCCAAGGCCTCAAGGCGCTCCA TGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGGGA GTTGCGCGCCGACACGGTTAACTCCTCCTCCAGAAGACGG ATGAGCTCGGCGACAGTGTCGCGCACCTCGCGCTCAAAGG CTACAGGGGCCTCTTCTTCTTCTTCAATCTCCTCTTCCATAA GGGCCTCCCCTTCTTCTTCTTCTGGCGGCGGTGGGGGAGGG GGGACACGGCGGCGACGACGGCGCACCGGGAGGCGGTCG ACAAAGCGCTCGATCATCTCCCCGCGGCGACGGCGCATGG TCTCGGTGACGGCGCGGCCGTTCTCGCGGGGGCGCAGTTG GAAGACGCCGCCCGTCATGTCCCGGTTATGGGTTGGCGGG GGGCTGCCATGCGGCAGGGATACGGCGCTAACGATGCATC TCAACAATTGTTGTGTAGGTACTCCGCCGCCGAGGGACCTG AGCGAGTCCGCATCGACCGGATCGGAAAACCTCTCGAGAA AGGCGTCTAACCAGTCACAGTCGCAAGGTAGGCTGAGCAC CGTGGCGGGCGGCAGCGGGCGGCGGTCGGGGTTGTTTCTG GCGGAGGTGCTGCTGATGATGTAATTAAAGTAGGCGGTCT TGAGACGGCGGATGGTCGACAGAAGCACCATGTCCTTGGG TCCGGCCTGCTGAATGCGCAGGCGGTCGGCCATGCCCCAG GCTTCGTTTTGACATCGGCGCAGGTCTTTGTAGTAGTCTTG CATGAGCCTTTCTACCGGCACTTCTTCTTCTCCTTCCTCTTG TCCTGCATCTCTTGCATCTATCGCTGCGGCGGCGGCGGAGT TTGGCCGTAGGTGGCGCCCTCTTCCTCCCATGCGTGTGACC CCGAAGCCCCTCATCGGCTGAAGCAGGGCTAGGTCGGCGA CAACGCGCTCGGCTAATATGGCCTGCTGCACCTGCGTGAG GGTAGACTGGAAGTCATCCATGTCCACAAAGCGGTGGTAT GCGCCCGTGTTGATGGTGTAAGTGCAGTTGGCCATAACGG ACCAGTTAACGGTCTGGTGACCCGGCTGCGAGAGCTCGGT GTACCTGAGACGCGAGTAAGCCCTCGAGTCAAATACGTAG TCGTTGCAAGTCCGCACCAGGTACTGGTATCCCACCAAAA AGTGCGGCGGCGGCTGGCGGTAGAGGGGCCAGCGTAGGGT GGCCGGGGCTCCGGGGGCGAGATCTTCCAACATAAGGCGA TGATATCCGTAGATGTACCTGGACATCCAGGTGATGCCGG CGGCGGTGGTGGAGGCGCGCGGAAAGTCGCGGACGCGGTT CCAGATGTTGCGCAGCGGCAAAAAGTGCTCCATGGTCGGG ACGCTCTGGCCGGTCAGGCGCGCGCAATCGTTGACGCTCT AGCGTGCAAAAGGAGAGCCTGTAAGCGGGCACTCTTCCGT GGTCTGGTGGATAAATTCGCAAGGGTATCATGGCGGACGA CCGGGGTTCGAGCCCCGTATCCGGCCGTCCGCCGTGATCCA TGCGGTTACCGCCCGCGTGTCGAACCCAGGTGTGCGACGT CAGACAACGGGGGAGTGCTCCTTTTGGCTTCCTTCCAGGCG CGGCGGCTGCTGCGCTAGCTTTTTTGGCCACTGGCCGCGCG CAGCGTAAGCGGTTAGGCTGGAAAGCGAAAGCATTAAGTG GCTCGCTCCCTGTAGCCGGAGGGTTATTTTCCAAGGGTTGA GTCGCGGGACCCCCGGTTCGAGTCTCGGACCGGCCGGACT GCGGCGAACGGGGGTTTGCCTCCCCGTCATGCAAGACCCC GCTTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTTTT GCTTTTCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCC CCTCCTCAGCAGCGGCAAGAGCAAGAGCAGCGGCAGACAT GCAGGGCACCCTCCCCTCCTCCTACCGCGTCAGGAGGGGC GACATCCGCGGTTGACGCGGCAGCAGATGGTGATTACGAA CCCCCGCGGCGCCGGGCCCGGCACTACCTGGACTTGGAGG AGGGCGAGGGCCTGGCGCGGCTAGGAGCGCCCTCTCCTGA GCGGCACCCAAGGGTGCAGCTGAAGCGTGATACGCGTGAG GCGTACGTGCCGCGGCAGAACCTGTTTCGCGACCGCGAGG GAGAGGAGCCCGAGGAGATGCGGGATCGAAAGTTCCACG CAGGGCGCGAGCTGCGGCATGGCCTGAATCGCGAGCGGTT GCTGCGCGAGGAGGACTTTGAGCCCGACGCGCGAACCGGG ATTAGTCCCGCGCGCGCACACGTGGCGGCCGCCGACCTGG TAACCGCATACGAGCAGACGGTGAACCAGGAGATTAACTT TCAAAAAAGCTTTAACAACCACGTGCGTACGCTTGTGGCG CGCGAGGAGGTGGCTATAGGACTGATGCATCTGTGGGACT TTGTAAGCGCGCTGGAGCAAAACCCAAATAGCAAGCCGCT CATGGCGCAGCTGTTCCTTATAGTGCAGCACAGCAGGGAC AACGAGGCATTCAGGGATGCGCTGCTAAACATAGTAGAGC CCGAGGGCCGCTGGCTGCTCGATTTGATAAACATCCTGCA GAGCATAGTGGTGCAGGAGCGCAGCTTGAGCCTGGCTGAC AAGGTGGCCGCCATCAACTATTCCATGCTTAGCCTGGGCA AGTTTTACGCCCGCAAGATATACCATACCCCTTACGTTCCC ATAGACAAGGAGGTAAAGATCGAGGGGTTCTACATGCGCA TGGCGCTGAAGGTGCTTACCTTGAGCGACGACCTGGGCGT TTATCGCAACGAGCGCATCCACAAGGCCGTGAGCGTGAGC CGGCGGCGCGAGCTCAGCGACCGCGAGCTGATGCACAGCC TGCAAAGGGCCCTGGCTGGCACGGGCAGCGGCGATAGAGA GGCCGAGTCCTACTTTGACGCGGGCGCTGACCTGCGCTGG GCCCCAAGCCGACGCGCCCTGGAGGCAGCTGGGGCCGGAC CTGGGCTGGCGGTGGCACCCGCGCGCGCTGGCAACGTCGG CGGCGTGGAGGAATATGACGAGGACGATGAGTACGAGCC AGAGGACGGCGAGTACTAAGCGGTGATGTTTCTGATCAGA TGATGCAAGACGCAACGGACCCGGCGGTGCGGGCGGCGCT GCAGAGCCAGCCGTCCGGCCTTAACTCCACGGACGACTGG CGCCAGGTCATGGACCGCATCATGTCGCTGACTGCGCGCA ATCCTGACGCGTTCCGGCAGCAGCCGCAGGCCAACCGGCT CTCCGCAATTCTGGAAGCGGTGGTCCCGGCGCGCGCAAAC CCCACGCACGAGAAGGTGCTGGCGATCGTAAACGCGCTGG CCGAAAACAGGGCCATCCGGCCCGACGAGGCCGGCCTGGT CTACGACGCGCTGCTTCAGCGCGTGGCTCGTTACAACAGC GGCAACGTGCAGACCAACCTGGACCGGCTGGTGGGGGATG TGCGCGAGGCCGTGGCGCAGCGTGAGCGCGCGCAGCAGCA GGGCAACCTGGGCTCCATGGTTGCACTAAACGCCTTCCTGA GTACACAGCCCGCCAACGTGCCGCGGGGACAGGAGGACTA CACCAACTTTGTGAGCGCACTGCGGCTAATGGTGACTGAG ACACCGCAAAGTGAGGTGTACCAGTCTGGGCCAGACTATT TTTTCCAGACCAGTAGACAAGGCCTGCAGACCGTAAACCT GAGCCAGGCTTTCAAAAACTTGCAGGGGCTGTGGGGGGTG CGGGCTCCCACAGGCGACCGCGCGACCGTGTCTAGCTTGC TGACGCCCAACTCGCGCCTGTTGCTGCTGCTAATAGCGCCC TTCACGGACAGTGGCAGCGTGTCCCGGGACACATACCTAG GTCACTTGCTGACACTGTACCGCGAGGCCATAGGTCAGGC GCATGTGGACGAGCATACTTTCCAGGAGATTACAAGTGTC AGCCGCGCGCTGGGGCAGGAGGACACGGGCAGCCTGGAG GCAACCCTAAACTACCTGCTGACCAACCGGCGGCAGAAGA TCCCCTCGTTGCACAGTTTAAACAGCGAGGAGGAGCGCAT TTTGCGCTACGTGCAGCAGAGCGTGAGCCTTAACCTGATGC GCGACGGGGTAACGCCCAGCGTGGCGCTGGACATGACCGC GCGCAACATGGAACCGGGCATGTATGCCTCAAACCGGCCG TTTATCAACCGCCTAATGGACTACTTGCATCGCGCGGCCGC CGTGAACCCCGAGTATTTCACCAATGCCATCTTGAACCCGC ACTGGCTACCGCCCCCTGGTTTCTACACCGGGGGATTCGAG GTGCCCGAGGGTAACGATGGATTCCTCTGGGACGACATAG ACGACAGCGTGTTTTCCCCGCAACCGCAGACCCTGCTAGA GTTGCAACAGCGCGAGCAGGCAGAGGCGGCGCTGCGAAA GGAAAGCTTCCGCAGGCCAAGCAGCTTGTCCGATCTAGGC GCTGCGGCCCCGCGGTCAGATGCTAGTAGCCCATTTCCAA GCTTGATAGGGTCTCTTACCAGCACTCGCACCACCCGCCCG CGCCTGCTGGGCGAGGAGGAGTACCTAAACAACTCGCTGC TGCAGCCGCAGCGCGAAAAAAACCTGCCTCCGGCATTTCC CAACAACGGGATAGAGAGCCTAGTGGACAAGATGAGTAG ATGGAAGACGTACGCGCAGGAGCACAGGGACGTGCCAGG CCCGCGCCCGCCCACCCGTCGTCAAAGGCACGACCGTCAG CGGGGTCTGGTGTGGGAGGACGATGACTCGGCAGACGACA GCAGCGTCCTGGATTTGGGAGGGAGTGGCAACCCGTTTGC GCACCTTCGCCCCAGGCTGGGGAGAATGTTTTAAAAAAAA AAAAGCATGATGCAAAATAAAAAACTCACCAAGGCCATGG CACCGAGCGTTGGTTTTCTTGTATTCCCCTTAGTATGCGGC GCGCGGCGATGTATGAGGAAGGTCCTCCTCCCTCCTACGA GAGTGTGGTGAGCGCGGCGCCAGTGGCGGCGGCGCTGGGT TCTCCCTTCGATGCTCCCCTGGACCCGCCGTTTGTGCCTCC GCGGTACCTGCGGCCTACCGGGGGGAGAAACAGCATCCGT TACTCTGAGTTGGCACCCCTATTCGACACCACCCGTGTGTA CCTGGTGGACAACAAGTCAACGGATGTGGCATCCCTGAAC TACCAGAACGACCACAGCAACTTTCTGACCACGGTCATTC

AAAACAATGACTACAGCCCGGGGGAGGCAAGCACACAGA CCATCAATCTTGACGACCGGTCGCACTGGGGCGGCGACCT GAAAACCATCCTGCATACCAACATGCCAAATGTGAACGAG TTCATGTTTACCAATAAGTTTAAGGCGCGGGTGATGGTGTC GCGCTTGCCTACTAAGGACAATCAGGTGGAGCTGAAATAC GAGTGGGTGGAGTTCACGCTGCCCGAGGGCAACTACTCCG AGACCATGACCATAGACCTTATGAACAACGCGATCGTGGA GCACTACTTGAAAGTGGGCAGACAGAACGGGGTTCTGGAA AGCGACATCGGGGTAAAGTTTGACACCCGCAACTTCAGAC TGGGGTTTGACCCCGTCACTGGTCTTGTCATGCCTGGGGTA TATACAAACGAAGCCTTCCATCCAGACATCATTTTGCTGCC AGGATGCGGGGTGGACTTCACCCACAGCCGCCTGAGCAAC TTGTTGGGCATCCGCAAGCGGCAACCCTTCCAGGAGGGCT TTAGGATCACCTACGATGATCTGGAGGGTGGTAACATTCCC GCACTGTTGGATGTGGACGCCTACCAGGCGAGCTTGAAAG ATGACACCGAACAGGGCGGGGGTGGCGCAGGCGGCAGCA ACAGCAGTGGCAGCGGCGCGGAAGAGAACTCCAACGCGG CAGCCGCGGCAATGCAGCCGGTGGAGGACATGAACGATCA TGCCATTCGCGGCGACACCTTTGCCACACGGGCTGAGGAG AAGCGCGCTGAGGCCGAAGCAGCGGCCGAAGCTGCCGCCC CCGCTGCGCAACCCGAGGTCGAGAAGCCTCAGAAGAAACC GGTGATCAAACCCCTGACAGAGGACAGCAAGAAACGCAGT TACAACCTAATAAGCAATGACAGCACCTTCACCCAGTACC GCAGCTGGTACCTTGCATACAACTACGGCGACCCTCAGAC CGGAATCCGCTCATGGACCCTGCTTTGCACTCCTGACGTAA CCTGCGGCTCGGAGCAGGTCTACTGGTCGTTGCCAGACAT GATGCAAGACCCCGTGACCTTCCGCTCCACGCGCCAGATC AGCAACTTTCCGGTGGTGGGCGCCGAGCTGTTGCCCGTGC ACTCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCA ACTCATCCGCCAGTTTACCTCTCTGACCCACGTGTTCAATC GCTTTCCCGAGAACCAGATTTTGGCGCGCCCGCCAGCCCCC ACCATCACCACCGTCAGTGAAAACGTTCCTGCTCTCACAGA TCACGGGACGCTACCGCTGCGCAACAGCATCGGAGGAGTC CAGCGAGTGACCATTACTGACGCCAGACGCCGCACCTGCC CCTACGTTTACAAGGCCCTGGGCATAGTCTCGCCGCGCGTC CTATCGAGCCGCACTTTTTGAGCAAGCATGTCCATCCTTAT ATCGCCCAGCAATAACACAGGCTGGGGCCTGCGCTTCCCA AGCAAGATGTTTGGCGGGGCCAAGAAGCGCTCCGACCAAC ACCCAGTGCGCGTGCGCGGGCACTACCGCGCGCCCTGGGG CGCGCACAAACGCGGCCGCACTGGGCGCACCACCGTCGAT GACGCCATCGACGCGGTGGTGGAGGAGGCGCGCAACTACA CGCCCACGCCGCCACCAGTGTCCACAGTGGACGCGGCCAT TCAGACCGTGGTGCGCGGAGCCCGGCGCTATGCTAAAATG AAGAGACGGCGGAGGCGCGTAGCACGTCGCCACCGCCGCC GACCCGGCACTGCCGCCCAACGCGCGGCGGCGGCCCTGCT TAACCGCGCACGTCGCACCGGCCGACGGGCGGCCATGCGG GCCGCTCGAAGGCTGGCCGCGGGTATTGTCACTGTGCCCCC CAGGTCCAGGCGACGAGCGGCCGCCGCAGCAGCCGCGGCC ATTAGTGCTATGACTCAGGGTCGCAGGGGCAACGTGTATT GGGTGCGCGACTCGGTTAGCGGCCTGCGCGTGCCCGTGCG CACCCGCCCCCCGCGCAACTAGATTGCAAGAAAAAACTAC TTAGACTCGTACTGTTGTATGTATCCAGCGGCGGCGGCGCG CAACGAAGCTATGTCCAAGCGCAAAATCAAAGAAGAGATG CTCCAGGTCATCGCGCCGGAGATCTATGGCCCCCCGAAGA AGGAAGAGCAGGATTACAAGCCCCGAAAGCTAAAGCGGG TCAAAAAGAAAAAGAAAGATGATGATGATGAACTTGACG ACGAGGTGGAACTGCTGCACGCTACCGCGCCCAGGCGACG GGTACAGTGGAAAGGTCGACGCGTAAAACGTGTTTTGCGA CCCGGCACCACCGTAGTCTTTACGCCCGGTGAGCGCTCCAC CCGCACCTACAAGCGCGTGTATGATGAGGTGTACGGCGAC GAGGACCTGCTTGAGCAGGCCAACGAGCGCCTCGGGGAGT TTGCCTACGGAAAGCGGCATAAGGACATGCTGGCGTTGCC GCTGGACGAGGGCAACCCAACACCTAGCCTAAAGCCCGTA ACACTGCAGCAGGTGCTGCCCGCGCTTGCACCGTCCGAAG AAAAGCGCGGCCTAAAGCGCGAGTCTGGTGACTTGGCACC CACCGTGCAGCTGATGGTACCCAAGCGCCAGCGACTGGAA GATGTCTTGGAAAAAATGACCGTGGAACCTGGGCTGGAGC CCGAGGTCCGCGTGCGGCCAATCAAGCAGGTGGCGCCGGG ACTGGGCGTGCAGACCGTGGACGTTCAGATACCCACTACC AGTAGCACCAGTATTGCCACCGCCACAGAGGGCATGGAGA CACAAACGTCCCCGGTTGCCTCAGCGGTGGCGGATGCCGC GGTGCAGGCGGTCGCTGCGGCCGCGTCCAAGACCTCTACG GAGGTGCAAACGGACCCGTGGATGTTTCGCGTTTCAGCCC CCCGGCGCCCGCGCCGTTCGAGGAAGTACGGCGCCGCCAG CGCGCTACTGCCCGAATATGCCCTACATCCTTCCATTGCGC CTACCCCCGGCTATCGTGGCTACACCTACCGCCCCAGAAG ACGAGCAACTACCCGACGCCGAACCACCACTGGAACCCGC CGCCGCCGTCGCCGTCGCCAGCCCGTGCTGGCCCCGATTTC CGTGCGCAGGGTGGCTCGCGAAGGAGGCAGGACCCTGGTG CTGCCAACAGCGCGCTACCACCCCAGCATCGTTTAAAAGC CGGTCTTTGTGGTTCTTGCAGATATGGCCCTCACCTGCCGC CTCCGTTTCCCGGTGCCGGGATTCCGAGGAAGAATGCACC GTAGGAGGGGCATGGCCGGCCACGGCCTGACGGGCGGCAT GCGTCGTGCGCACCACCGGCGGCGGCGCGCGTCGCACCGT CGCATGCGCGGCGGTATCCTGCCCCTCCTTATTCCACTGAT CGCCGCGGCGATTGGCGCCGTGCCCGGAATTGCATCCGTG GCCTTGCAGGCGCAGAGACACTGATTAAAAACAAGTTGCA TGTGGAAAAATCAAAATAAAAAGTCTGGACTCTCACGCTC GCTTGGTCCTGTAACTATTTTGTAGAATGGAAGACATCAAC TTTGCGTCTCTGGCCCCGCGACACGGCTCGCGCCCGTTCAT GGGAAACTGGCAAGATATCGGCACCAGCAATATGAGCGGT GGCGCCTTCAGCTGGGGCTCGCTGTGGAGCGGCATTAAAA ATTTCGGTTCCACCGTTAAGAACTATGGCAGCAAGGCCTG GAACAGCAGCACAGGCCAGATGCTGAGGGATAAGTTGAA AGAGCAAAATTTCCAACAAAAGGTGGTAGATGGCCTGGCC TCTGGCATTAGCGGGGTGGTGGACCTGGCCAACCAGGCAG TGCAAAATAAGATTAACAGTAAGCTTGATCCCCGCCCTCCC GTAGAGGAGCCTCCACCGGCCGTGGAGACAGTGTCTCCAG AGGGGCGTGGCGAAAAGCGTCCGCGCCCCGACAGGGAAG AAACTCTGGTGACGCAAATAGACGAGCCTCCCTCGTACGA GGAGGCACTAAAGCAAGGCCTGCCCACCACCCGTCCCATC GCGCCCATGGCTACCGGAGTGCTGGGCCAGCACACACCCG TAACGCTGGACCTGCCTCCCCCCGCCGACACCCAGCAGAA ACCTGTGCTGCCAGGCCCGACCGCCGTTGTTGTAACCCGTC CTAGCCGCGCGTCCCTGCGCCGCGCCGCCAGCGGTCCGCG ATCGTTGCGGCCCGTAGCCAGTGGCAACTGGCAAAGCACA CTGAACAGCATCGTGGGTCTGGGGGTGCAATCCCTGAAGC GCCGACGATGCTTCTGATAGCTAACGTGTCGTATGTGTGTC ATGTATGCGTCCATGTCGCCGCCAGAGGAGCTGCTGAGCC GCCGCGCGCCCGCTTTCCAAGATGGCTACCCCTTCGATGAT GCCGCAGTGGTCTTACATGCACATCTCGGGCCAGGACGCC TCGGAGTACCTGAGCCCCGGGCTGGTGCAGTTTGCCCGCG CCACCGAGACGTACTTCAGCCTGAATAACAAGTTTAGAAA CCCCACGGTGGCGCCTACGCACGACGTGACCACAGACCGG TCCCAGCGTTTGACGCTGCGGTTCATCCCTGTGGACCGTGA GGATACTGCGTACTCGTACAAGGCGCGGTTCACCCTAGCT GTGGGTGATAACCGTGTGCTGGACATGGCTTCCACGTACTT TGACATCCGCGGCGTGCTGGACAGGGGCCCTACTTTTAAG CCCTACTCTGGCACTGCCTACAACGCCCTGGCTCCCAAGGG TGCCCCAAATCCTTGCGAATGGGATGAAGCTGCTACTGCTC TTGAAATAAACCTAGAAGAAGAGGACGATGACAACGAAG ACGAAGTAGACGAGCAAGCTGAGCAGCAAAAAACTCACG TATTTGGGCAGGCGCCTTATTCTGGTATAAATATTACAAAG GAGGGTATTCAAATAGGTGTCGAAGGTCAAACACCTAAAT ATGCCGATAAAACATTTCAACCTGAACCTCAAATAGGAGA ATCTCAGTGGTACGAAACAGAAATTAATCATGCAGCTGGG AGAGTCCTAAAAAAGACTACCCCAATGAAACCATGTTACG GTTCATATGCAAAACCCACAAATGAAAATGGAGGGCAAGG CATTCTTGTAAAGCAACAAAATGGAAAGCTAGAAAGTCAA GTGGAAATGCAATTTTTCTCAACTACTGAGGCAGCCGCAG GCAATGGTGATAACTTGACTCCTAAAGTGGTATTGTACAGT GAAGATGTAGATATAGAAACCCCAGACACTCATATTTCTT ACATGCCCACTATTAAGGAAGGTAACTCACGAGAACTAAT GGGCCAACAATCTATGCCCAACAGGCCTAATTACATTGCTT TTAGGGACAATTTTATTGGTCTAATGTATTACAACAGCACG GGTAATATGGGTGTTCTGGCGGGCCAAGCATCGCAGTTGA ATGCTGTTGTAGATTTGCAAGACAGAAACACAGAGCTTTC ATACCAGCTTTTGCTTGATTCCATTGGTGATAGAACCAGGT ACTTTTCTATGTGGAATCAGGCTGTTGACAGCTATGATCCA GATGTTAGAATTATTGAAAATCATGGAACTGAAGATGAAC TTCCAAATTACTGCTTTCCACTGGGAGGTGTGATTAATACA GAGACTCTTACCAAGGTAAAACCTAAAACAGGTCAGGAAA ATGGATGGGAAAAAGATGCTACAGAATTTTCAGATAAAAA TGAAATAAGAGTTGGAAATAATTTTGCCATGGAAATCAAT CTAAATGCCAACCTGTGGAGAAATTTCCTGTACTCCAACAT AGCGCTGTATTTGCCCGACAAGCTAAAGTACAGTCCTTCCA ACGTAAAAATTTCTGATAACCCAAACACCTACGACTACAT GAACAAGCGAGTGGTGGCTCCCGGGCTAGTGGACTGCTAC ATTAACCTTGGAGCACGCTGGTCCCTTGACTATATGGACAA CGTCAACCCATTTAACCACCACCGCAATGCTGGCCTGCGCT ACCGCTCAATGTTGCTGGGCAATGGTCGCTATGTGCCCTTC CACATCCAGGTGCCTCAGAAGTTCTTTGCCATTAAAAACCT CCTTCTCCTGCCGGGCTCATACACCTACGAGTGGAACTTCA GGAAGGATGTTAACATGGTTCTGCAGAGCTCCCTAGGAAA TGACCTAAGGGTTGACGGAGCCAGCATTAAGTTTGATAGC ATTTGCCTTTACGCCACCTTCTTCCCCATGGCCCACAACAC CGCCTCCACGCTTGAGGCCATGCTTAGAAACGACACCAAC GACCAGTCCTTTAACGACTATCTCTCCGCCGCCAACATGCT CTACCCTATACCCGCCAACGCTACCAACGTGCCCATATCCA TCCCCTCCCGCAACTGGGCGGCTTTCCGCGGCTGGGCCTTC ACGCGCCTTAAGACTAAGGAAACCCCATCACTGGGCTCGG GCTACGACCCTTATTACACCTACTCTGGCTCTATACCCTAC CTAGATGGAACCTTTTACCTCAACCACACCTTTAAGAAGGT GGCCATTACCTTTGACTCTTCTGTCAGCTGGCCTGGCAATG ACCGCCTGCTTACCCCCAACGAGTTTGAAATTAAGCGCTCA GTTGACGGGGAGGGTTACAACGTTGCCCAGTGTAACATGA CCAAAGACTGGTTCCTGGTACAAATGCTAGCTAACTATAA CATTGGCTACCAGGGCTTCTATATCCCAGAGAGCTACAAG GACCGCATGTACTCCTTCTTTAGAAACTTCCAGCCCATGAG CCGTCAGGTGGTGGATGATACTAAATACAAGGACTACCAA CAGGTGGGCATCCTACACCAACACAACAACTCTGGATTTG TTGGCTACCTTGCCCCCACCATGCGCGAAGGACAGGCCTA CCCTGCTAACTTCCCCTATCCGCTTATAGGCAAGACCGCAG TTGACAGCATTACCCAGAAAAAGTTTCTTTGCGATCGCACC CTTTGGCGCATCCCATTCTCCAGTAACTTTATGTCCATGGG CGCACTCACAGACCTGGGCCAAAACCTTCTCTACGCCAACT CCGCCCACGCGCTAGACATGACTTTTGAGGTGGATCCCATG GACGAGCCCACCCTTCTTTATGTTTTGTTTGAAGTCTTTGAC GTGGTCCGTGTGCACCAGCCGCACCGCGGCGTCATCGAAA CCGTGTACCTGCGCACGCCCTTCTCGGCCGGCAACGCCACA ACATAAAGAAGCAAGCAACATCAACAACAGCTGCCGCCAT GGGCTCCAGTGAGCAGGAACTGAAAGCCATTGTCAAAGAT CTTGGTTGTGGGCCATATTTTTTGGGCACCTATGACAAGCG CTTTCCAGGCTTTGTTTCTCCACACAAGCTCGCCTGCGCCA TAGTCAATACGGCCGGTCGCGAGACTGGGGGCGTACACTG GATGGCCTTTGCCTGGAACCCGCACTCAAAAACATGCTAC CTCTTTGAGCCCTTTGGCTTTTCTGACCAGCGACTCAAGCA GGTTTACCAGTTTGAGTACGAGTCACTCCTGCGCCGTAGCG CCATTGCTTCTTCCCCCGACCGCTGTATAACGCTGGAAAAG TCCACCCAAAGCGTACAGGGGCCCAACTCGGCCGCCTGTG GACTATTCTGCTGCATGTTTCTCCACGCCTTTGCCAACTGG CCCCAAACTCCCATGGATCACAACCCCACCATGAACCTTAT TACCGGGGTACCCAACTCCATGCTCAACAGTCCCCAGGTA CAGCCCACCCTGCGTCGCAACCAGGAACAGCTCTACAGCT TCCTGGAGCGCCACTCGCCCTACTTCCGCAGCCACAGTGCG CAGATTAGGAGCGCCACTTCTTTTTGTCACTTGAAAAACAT GTAAAAATAATGTACTAGAGACACTTTCAATAAAGGCAAA TGCTTTTATTTGTACACTCTCGGGTGATTATTTACCCCCACC CTTGCCGTCTGCGCCGTTTAAAAATCAAAGGGGTTCTGCCG CGCATCGCTATGCGCCACTGGCAGGGACACGTTGCGATAC TGGTGTTTAGTGCTCCACTTAAACTCAGGCACAACCATCCG CGGCAGCTCGGTGAAGTTTTCACTCCACAGGCTGCGCACC ATCACCAACGCGTTTAGCAGGTCGGGCGCCGATATCTTGA AGTCGCAGTTGGGGCCTCCGCCCTGCGCGCGCGAGTTGCG ATACACAGGGTTGCAGCACTGGAACACTATCAGCGCCGGG TGGTGCACGCTGGCCAGCACGCTCTTGTCGGAGATCAGAT CCGCGTCCAGGTCCTCCGCGTTGCTCAGGGCGAACGGAGT CAACTTTGGTAGCTGCCTTCCCAAAAAGGGCGCGTGCCCA GGCTTTGAGTTGCACTCGCACCGTAGTGGCATCAAAAGGT GACCGTGCCCGGTCTGGGCGTTAGGATACAGCGCCTGCAT AAAAGCCTTGATCTGCTTAAAAGCCACCTGAGCCTTTGCGC CTTCAGAGAAGAACATGCCGCAAGACTTGCCGGAAAACTG ATTGGCCGGACAGGCCGCGTCGTGCACGCAGCACCTTGCG TCGGTGTTGGAGATCTGCACCACATTTCGGCCCCACCGGTT CTTCACGATCTTGGCCTTGCTAGACTGCTCCTTCAGCGCGC GCTGCCCGTTTTCGCTCGTCACATCCATTTCAATCACGTGC TCCTTATTTATCATAATGCTTCCGTGTAGACACTTAAGCTC GCCTTCGATCTCAGCGCAGCGGTGCAGCCACAACGCGCAG CCCGTGGGCTCGTGATGCTTGTAGGTCACCTCTGCAAACGA CTGCAGGTACGCCTGCAGGAATCGCCCCATCATCGTCACA AAGGTCTTGTTGCTGGTGAAGGTCAGCTGCAACCCGCGGT GCTCCTCGTTCAGCCAGGTCTTGCATACGGCCGCCAGAGCT TCCACTTGGTCAGGCAGTAGTTTGAAGTTCGCCTTTAGATC GTTATCCACGTGGTACTTGTCCATCAGCGCGCGCGCAGCCT CCATGCCCTTCTCCCACGCAGACACGATCGGCACACTCAGC GGGTTCATCACCGTAATTTCACTTTCCGCTTCGCTGGGCTC TTCCTCTTCCTCTTGCGTCCGCATACCACGCGCCACTGGGT CGTCTTCATTCAGCCGCCGCACTGTGCGCTTACCTCCTTTG CCATGCTTGATTAGCACCGGTGGGTTGCTGAAACCCACCAT TTGTAGCGCCACATCTTCTCTTTCTTCCTCGCTGTCCACGAT TACCTCTGGTGATGGCGGGCGCTCGGGCTTGGGAGAAGGG CGCTTCTTTTTCTTCTTGGGCGCAATGGCCAAATCCGCCGC CGAGGTCGATGGCCGCGGGCTGGGTGTGCGCGGCACCAGC GCGTCTTGTGATGAGTCTTCCTCGTCCTCGGACTCGATACG CCGCCTCATCCGCTTTTTTGGGGGCGCCCGGGGAGGCGGC GGCGACGGGGACGGGGACGACACGTCCTCCATGGTTGGGG GACGTCGCGCCGCACCGCGTCCGCGCTCGGGGGTGGTTTC GCGCTGCTCCTCTTCCCGACTGGCCATTTCCTTCTCCTATAG GCAGAAAAAGATCATGGAGTCAGTCGAGAAGAAGGACAG CCTAACCGCCCCCTCTGAGTTCGCCACCACCGCCTCCACCG ATGCCGCCAACGCGCCTACCACCTTCCCCGTCGAGGCACCC CCGCTTGAGGAGGAGGAAGTGATTATCGAGCAGGACCCAG GTTTTGTAAGCGAAGACGACGAGGACCGCTCAGTACCAAC AGAGGATAAAAAGCAAGACCAGGACAACGCAGAGGCAAA CGAGGAACAAGTCGGGCGGGGGGACGAAAGGCATGGCGA CTACCTAGATGTGGGAGACGACGTGCTGTTGAAGCATCTG CAGCGCCAGTGCGCCATTATCTGCGACGCGTTGCAAGAGC GCAGCGATGTGCCCCTCGCCATAGCGGATGTCAGCCTTGCC TACGAACGCCACCTATTCTCACCGCGCGTACCCCCCAAACG CCAAGAAAACGGCACATGCGAGCCCAACCCGCGCCTCAAC TTCTACCCCGTATTTGCCGTGCCAGAGGTGCTTGCCACCTA

TCACATCTTTTTCCAAAACTGCAAGATACCCCTATCCTGCC GTGCCAACCGCAGCCGAGCGGACAAGCAGCTGGCCTTGCG GCAGGGCGCTGTCATACCTGATATCGCCTCGCTCAACGAA GTGCCAAAAATCTTTGAGGGTCTTGGACGCGACGAGAAGC GCGCGGCAAACGCTCTGCAACAGGAAAACAGCGAAAATG AAAGTCACTCTGGAGTGTTGGTGGAACTCGAGGGTGACAA CGCGCGCCTAGCCGTACTAAAACGCAGCATCGAGGTCACC CACTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCAT GAGCACAGTCATGAGTGAGCTGATCGTGCGCCGTGCGCAG CCCCTGGAGAGGGATGCAAATTTGCAAGAACAAACAGAGG AGGGCCTACCCGCAGTTGGCGACGAGCAGCTAGCGCGCTG GCTTCAAACGCGCGAGCCTGCCGACTTGGAGGAGCGACGC AAACTAATGATGGCCGCAGTGCTCGTTACCGTGGAGCTTG AGTGCATGCAGCGGTTCTTTGCTGACCCGGAGATGCAGCG CAAGCTAGAGGAAACATTGCACTACACCTTTCGACAGGGC TACGTACGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCT GCAACCTGGTCTCCTACCTTGGAATTTTGCACGAAAACCGC CTTGGGCAAAACGTGCTTCATTCCACGCTCAAGGGCGAGG CGCGCCGCGACTACGTCCGCGACTGCGTTTACTTATTTCTA TGCTACACCTGGCAGACGGCCATGGGCGTTTGGCAGCAGT GCTTGGAGGAGTGCAACCTCAAGGAGCTGCAGAAACTGCT AAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACGAG CGCTCCGTGGCCGCGCACCTGGCGGACATCATTTTCCCCGA ACGCCTGCTTAAAACCCTGCAACAGGGTCTGCCAGACTTC ACCAGTCAAAGCATGTTGCAGAACTTTAGGAACTTTATCCT AGAGCGCTCAGGAATCTTGCCCGCCACCTGCTGTGCACTTC CTAGCGACTTTGTGCCCATTAAGTACCGCGAATGCCCTCCG CCGCTTTGGGGCCACTGCTACCTTCTGCAGCTAGCCAACTA CCTTGCCTACCACTCTGACATAATGGAAGACGTGAGCGGT GACGGTCTACTGGAGTGTCACTGTCGCTGCAACCTATGCAC CCCGCACCGCTCCCTGGTTTGCAATTCGCAGCTGCTTAACG AAAGTCAAATTATCGGTACCTTTGAGCTGCAGGGTCCCTCG CCTGACGAAAAGTCCGCGGCTCCGGGGTTGAAACTCACTC CGGGGCTGTGGACGTCGGCTTACCTTCGCAAATTTGTACCT GAGGACTACCACGCCCACGAGATTAGGTTCTACGAAGACC AATCCCGCCCGCCTAATGCGGAGCTTACCGCCTGCGTCATT ACCCAGGGCCACATTCTTGGCCAATTGCAAGCCATCAACA AAGCCCGCCAAGAGTTTCTGCTACGAAAGGGACGGGGGGT TTACTTGGACCCCCAGTCCGGCGAGGAGCTCAACCCAATC CCCCCGCCGCCGCAGCCCTATCAGCAGCAGCCGCGGGCCC TTGCTTCCCAGGATGGCACCCAAAAAGAAGCTGCAGCTGC CGCCGCCACCCACGGACGAGGAGGAATACTGGGACAGTCA GGCAGAGGAGGTTTTGGACGAGGAGGAGGAGGACATGAT GGAAGACTGGGAGAGCCTAGACGAGGAAGCTTCCGAGGTC GAAGAGGTGTCAGACGAAACACCGTCACCCTCGGTCGCAT TCCCCTCGCCGGCGCCCCAGAAATCGGCAACCGGTTCCAG CATGGCTACAACCTCCGCTCCTCAGGCGCCGCCGGCACTGC CCGTTCGCCGACCCAACCGTAGATGGGACACCACTGGAAC CAGGGCCGGTAAGTCCAAGCAGCCGCCGCCGTTAGCCCAA GAGCAACAACAGCGCCAAGGCTACCGCTCATGGCGCGGGC ACAAGAACGCCATAGTTGCTTGCTTGCAAGACTGTGGGGG CAACATCTCCTTCGCCCGCCGCTTTCTTCTCTACCATCACG GCGTGGCCTTCCCCCGTAACATCCTGCATTACTACCGTCAT CTCTACAGCCCATACTGCACCGGCGGCAGCGGCAGCAACA GCAGCGGCCACACAGAAGCAAAGGCGACCGGATAGCAAG ACTCTGACAAAGCCCAAGAAATCCACAGCGGCGGCAGCAG CAGGAGGAGGAGCGCTGCGTCTGGCGCCCAACGAACCCGT ATCGACCCGCGAGCTTAGAAACAGGATTTTTCCCACTCTGT ATGCTATATTTCAACAGAGCAGGGGCCAAGAACAAGAGCT GAAAATAAAAAACAGGTCTCTGCGATCCCTCACCCGCAGC TGCCTGTATCACAAAAGCGAAGATCAGCTTCGGCGCACGC TGGAAGACGCGGAGGCTCTCTTCAGTAAATACTGCGCGCT GACTCTTAAGGACTAGTTTCGCGCCCTTTCTCAAATTTAAG CGCGAAAACTACGTCATCTCCAGCGGCCACACCCGGCGCC AGCACCTGTTGTCAGCGCCATTATGAGCAAGGAAATTCCC ACGCCCTACATGTGGAGTTACCAGCCACAAATGGGACTTG CGGCTGGAGCTGCCCAAGACTACTCAACCCGAATAAACTA CATGAGCGCGGGACCCCACATGATATCCCGGGTCAACGGA ATACGCGCCCACCGAAACCGAATTCTCCTGGAACAGGCGG CTATTACCACCACACCTCGTAATAACCTTAATCCCCGTAGT TGGCCCGCTGCCCTGGTGTACCAGGAAAGTCCCGCTCCCAC CACTGTGGTACTTCCCAGAGACGCCCAGGCCGAAGTTCAG ATGACTAACTCAGGGGCGCAGCTTGCGGGCGGCTTTCGTC ACAGGGTGCGGTCGCCCGGGCAGGGTATAACTCACCTGAC AATCAGAGGGCGAGGTATTCAGCTCAACGACGAGTCGGTG AGCTCCTCGCTTGGTCTCCGTCCGGACGGGACATTTCAGAT CGGCGGCGCCGGCCGCTCTTCATTCACGCCTCGTCAGGCAA TCCTAACTCTGCAGACCTCGTCCTCTGAGCCGCGCTCTGGA GGCATTGGAACTCTGCAATTTATTGAGGAGTTTGTGCCATC GGTCTACTTTAACCCCTTCTCGGGACCTCCCGGCCACTATC CGGATCAATTTATTCCTAACTTTGACGCGGTAAAGGACTCG GCGGACGGCTACGACTGAATGTTAAGTGGAGAGGCAGAGC AACTGCGCCTGAAACACCTGGTCCACTGTCGCCGCCACAA GTGCTTTGCCCGCGACTCCGGTGAGTTTTGCTACTTTGAAT TGCCCGAGGATCATATCGAGGGCCCGGCGCACGGCGTCCG GCTTACCGCCCAGGGAGAGCTTGCCCGTAGCCTGATTCGG GAGTTTACCCAGCGCCCCCTGCTAGTTGAGCGGGACAGGG GACCCTGTGTTCTCACTGTGATTTGCAACTGTCCTAACCCT GGATTACATCAAGATCCTCTAGTTAATGTCAGGTCGCCTAA GTCGATTAACTAGAGTACCCGGGGATCTTATTCCCTTTAAC TAATAAAAAAAAATAATAAAGCATCACTTACTTAAAATCA GTTAGCAAATTTCTGTCCAGTTTATTCAGCAGCACCTCCTT GCCCTCCTCCCAGCTCTGGTATTGCAGCTTCCTCCTGGCTG CAAACTTTCTCCACAATCTAAATGGAATGTCAGTTTCCTCC TGTTCCTGTCCATCCGCACCCACTATCTTCATGTTGTTGCAG ATGAAGCGCGCAAGACCGTCTGAAGATACCTTCAACCCCG TGTATCCATATGACACGGAAACCGGTCCTCCAACTGTGCCT TTTCTTACTCCTCCCTTTGTATCCCCCAATGGGTTTCAAGAG AGTCCCCCTGGGGTACTCTCTTTGCGCCTATCCGAACCTCT AGTTACCTCCAATGGCATGCTTGCGCTCAAAATGGGCAAC GGCCTCTCTCTGGACGAGGCCGGCAACCTTACCTCCCAAA ATGTAACCACTGTGAGCCCACCTCTCAAAAAAACCAAGTC AAACATAAACCTGGAAATATCTGCACCCCTCACAGTTACCT CAGAAGCCCTAACTGTGGCTGCCGCCGCACCTCTAATGGTC GCGGGCAACACACTCACCATGCAATCACAGGCCCCGCTAA CCGTGCACGACTCCAAACTTAGCATTGCCACCCAAGGACC CCTCACAGTGTCAGAAGGAAAGCTAGCCCTGCAAACATCA GGCCCCCTCACCACCACCGATAGCAGTACCCTTACTATCAC TGCCTCACCCCCTCTAACTACTGCCACTGGTAGCTTGGGCA TTGACTTGAAAGAGCCCATTTATACACAAAATGGAAAACT AGGACTAAAGTACGGGGCTCCTTTGCATGTAACAGACGAC CTAAACACTTTGACCGTAGCAACTGGTCCAGGTGTGACTAT TAATAATACTTCCTTGCAAACTAAAGTTACTGGAGCCTTGG GTTTTGATTCACAAGGCAATATGCAACTTAATGTAGCAGG AGGACTAAGGATTGATTCTCAAAACAGACGCCTTATACTT GATGTTAGTTATCCGTTTGATGCTCAAAACCAACTAAATCT AAGACTAGGACAGGGCCCTCTTTTTATAAACTCAGCCCAC AACTTGGATATTAACTACAACAAAGGCCTTTACTTGTTTAC AGCTTCAAACAATTCCAAAAAGCTTGAGGTTAACCTAAGC ACTGCCAAGGGGTTGATGTTTGACGCTACAGCCATAGCCA TTAATGCAGGAGATGGGCTTGAATTTGGTTCACCTAATGCA CCAAACACAAATCCCCTCAAAACAAAAATTGGCCATGGCC TAGAATTTGATTCAAACAAGGCTATGGTTCCTAAACTAGG AACTGGCCTTAGTTTTGACAGCACAGGTGCCATTACAGTAG GAAACAAAAATAATGATAAGCTAACTTTGTGGACCACACC AGCTCCATCTCCTAACTGTAGACTAAATGCAGAGAAAGAT GCTAAACTCACTTTGGTCTTAACAAAATGTGGCAGTCAAAT ACTTGCTACAGTTTCAGTTTTGGCTGTTAAAGGCAGTTTGG CTCCAATATCTGGAACAGTTCAAAGTGCTCATCTTATTATA AGATTTGACGAAAATGGAGTGCTACTAAACAATTCCTTCCT GGACCCAGAATATTGGAACTTTAGAAATGGAGATCTTACT GAAGGCACAGCCTATACAAACGCTGTTGGATTTATGCCTA ACCTATCAGCTTATCCAAAATCTCACGGTAAAACTGCCAA AAGTAACATTGTCAGTCAAGTTTACTTAAACGGAGACAAA ACTAAACCTGTAACACTAACCATTACACTAAACGGTACAC AGGAAACAGGAGACACAACTCCAAGTGCATACTCTATGTC ATTTTCATGGGACTGGTCTGGCCACAACTACATTAATGAAA TATTTGCCACATCCTCTTACACTTTTTCATACATTGCCCAAG AATAAAGAATCGTTTGTGTTATGTTTCAACGTGTTTATTTTT CAATTGCAGAAAATTTCAAGTCATTTTTCATTCAGTAGTAT AGCCCCACCACCACATAGCTTATACAGATCACCGTACCTTA ATCAAACTCACAGAACCCTAGTATTCAACCTGCCACCTCCC TCCCAACACACAGAGTACACAGTCCTTTCTCCCCGGCTGGC CTTAAAAAGCATCATATCATGGGTAACAGACATATTCTTAG GTGTTATATTCCACACGGTTTCCTGTCGAGCCAAACGCTCA TCAGTGATATTAATAAACTCCCCGGGCAGCTCACTTAAGTT CATGTCGCTGTCCAGCTGCTGAGCCACAGGCTGCTGTCCAA CTTGCGGTTGCTTAACGGGCGGCGAAGGAGAAGTCCACGC CTACATGGGGGTAGAGTCATAATCGTGCATCAGGATAGGG CGGTGGTGCTGCAGCAGCGCGCGAATAAACTGCTGCCGCC GCCGCTCCGTCCTGCAGGAATACAACATGGCAGTGGTCTC CTCAGCGATGATTCGCACCGCCCGCAGCATAAGGCGCCTT GTCCTCCGGGCACAGCAGCGCACCCTGATCTCACTTAAATC AGCACAGTAACTGCAGCACAGCACCACAATATTGTTCAAA ATCCCACAGTGCAAGGCGCTGTATCCAAAGCTCATGGCGG GGACCACAGAACCCACGTGGCCATCATACCACAAGCGCAG GTAGATTAAGTGGCGACCCCTCATAAACACGCTGGACATA AACATTACCTCTTTTGGCATGTTGTAATTCACCACCTCCCG GTACCATATAAACCTCTGATTAAACATGGCGCCATCCACCA CCATCCTAAACCAGCTGGCCAAAACCTGCCCGCCGGCTAT ACACTGCAGGGAACCGGGACTGGAACAATGACAGTGGAG AGCCCAGGACTCGTAACCATGGATCATCATGCTCGTCATG ATATCAATGTTGGCACAACACAGGCACACGTGCATACACT TCCTCAGGATTACAAGCTCCTCCCGCGTTAGAACCATATCC CAGGGAACAACCCATTCCTGAATCAGCGTAAATCCCACAC TGCAGGGAAGACCTCGCACGTAACTCACGTTGTGCATTGTC AAAGTGTTACATTCGGGCAGCAGCGGATGATCCTCCAGTA TGGTAGCGCGGGTTTCTGTCTCAAAAGGAGGTAGACGATC CCTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTT GGTCGTAGTGTCATGCCAAATGGAACGCCGGACGTAGTCA TATTTCCTGAAGCAAAACCAGGTGCGGGCGTGACAAACAG ATCTGCGTCTCCGGTCTCGCCGCTTAGATCGCTCTGTGTAG TAGTTGTAGTATATCCACTCTCTCAAAGCATCCAGGCGCCC CCTGGCTTCGGGTTCTATGTAAACTCCTTCATGCGCCGCTG CCCTGATAACATCCACCACCGCAGAATAAGCCACACCCAG CCAACCTACACATTCGTTCTGCGAGTCACACACGGGAGGA GCGGGAAGAGCTGGAAGAACCATGTTTTTTTTTTTATTCCA AAAGATTATCCAAAACCTCAAAATGAAGATCTATTAAGTG AACGCGCTCCCCTCCGGTGGCGTGGTCAAACTCTACAGCC AAAGAACAGATAATGGCATTTGTAAGATGTTGCACAATGG CTTCCAAAAGGCAAACGGCCCTCACGTCCAAGTGGACGTA AAGGCTAAACCCTTCAGGGTGAATCTCCTCTATAAACATTC CAGCACCTTCAACCATGCCCAAATAATTCTCATCTCGCCAC CTTCTCAATATATCTCTAAGCAAATCCCGAATATTAAGTCC GGCCATTGTAAAAATCTGCTCCAGAGCGCCCTCCACCTTCA GCCTCAAGCAGCGAATCATGATTGCAAAAATTCAGGTTCC TCACAGACCTGTATAAGATTCAAAAGCGGAACATTAACAA AAATACCGCGATCCCGTAGGTCCCTTCGCAGGGCCAGCTG AACATAATCGTGCAGGTCTGCACGGACCAGCGCGGCCACT TCCCCGCCAGGAACCATGACAAAAGAACCCACACTGATTA TGACACGCATACTCGGAGCTATGCTAACCAGCGTAGCCCC GATGTAAGCTTGTTGCATGGGCGGCGATATAAAATGCAAG GTGCTGCTCAAAAAATCAGGCAAAGCCTCGCGCAAAAAAG AAAGCACATCGTAGTCATGCTCATGCAGATAAAGGCAGGT AAGCTCCGGAACCACCACAGAAAAAGACACCATTTTTCTC TCAAACATGTCTGCGGGTTTCTGCATAAACACAAAATAAA ATAACAAAAAAACATTTAAACATTAGAAGCCTGTCTTACA ACAGGAAAAACAACCCTTATAAGCATAAGACGGACTACGG CCATGCCGGCGTGACCGTAAAAAAACTGGTCACCGTGATT AAAAAGCACCACCGACAGCTCCTCGGTCATGTCCGGAGTC ATAATGTAAGACTCGGTAAACACATCAGGTTGATTCACAT CGGTCAGTGCTAAAAAGCGACCGAAATAGCCCGGGGGAAT ACATACCCGCAGGCGTAGAGACAACATTACAGCCCCCATA GGAGGTATAACAAAATTAATAGGAGAGAAAAACACATAA ACACCTGAAAAACCCTCCTGCCTAGGCAAAATAGCACCCT CCCGCTCCAGAACAACATACAGCGCTTCCACAGCGGCAGC CATAACAGTCAGCCTTACCAGTAAAAAAGAAAACCTATTA AAAAAACACCACTCGACACGGCACCAGCTCAATCAGTCAC AGTGTAAAAAAGGGCCAAGTGCAGAGCGAGTATATATAGG ACTAAAAAATGACGTAACGGTTAAAGTCCACAAAAAACAC CCAGAAAACCGCACGCGAACCTACGCCCAGAAACGAAAG CCAAAAAACCCACAACTTCCTCAAATCGTCACTTCCGTTTT CCCACGTTACGTCACTTCCCATTTTAAGAAAACTACAATTC CCAACACATACAAGTTACTCCGCCCTAAAACCTACGTCACC CGCCCCGTTCCCACGCCCCGCGCCACGTCACAAACTCCACC CCCTCATTATCATATTGGCTTCAATCCAAAATAAGGTATAT TATTGATGAT 96 human IL-12 DNA GTCGACGCCACCATGTGTCACCAGCAGCTCGTGATTAGCT insert Sequence GGTTCAGCCTGGTGTTTCTGGCTAGCCCTCTGGTGGCCATC (including TGGGAGCTGAAGAAGGACGTGTACGTGGTGGAGCTCGACT restriction sites GGTACCCTGACGCTCCCGGCGAGATGGTCGTGCTGACCTG and Kozak CGACACCCCTGAGGAAGATGGCATCACCTGGACCCTGGAT sequence) CAAAGCTCCGAAGTGCTCGGCAGCGGCAAGACACTCACCA TCCAGGTGAAAGAGTTCGGAGACGCCGGCCAGTACACCTG CCACAAAGGCGGCGAGGTGCTGTCCCATTCCCTGCTGCTGC TGCACAAGAAAGAGGATGGCATCTGGTCCACCGACATCCT GAAGGACCAGAAGGAACCCAAGAACAAGACCTTTCTGAG ATGTGAGGCCAAGAACTACAGCGGCAGGTTCACCTGCTGG TGGCTGACAACAATCTCCACCGACCTGACCTTCAGCGTCAA GAGCAGCAGGGGCAGCAGCGACCCTCAAGGCGTGACATGT GGAGCCGCTACCCTGAGCGCTGAGAGAGTCAGGGGCGACA ATAAGGAGTACGAGTACTCCGTGGAATGCCAGGAGGACTC CGCCTGCCCTGCCGCCGAAGAGTCCCTCCCTATCGAAGTGA TGGTTGATGCCGTGCACAAGCTCAAGTATGAGAATTACAC CAGCAGCTTTTTCATCAGGGACATCATCAAGCCCGACCCCC CCAAAAACCTCCAGCTGAAACCCCTCAAGAATAGCAGGCA GGTGGAGGTCTCCTGGGAGTATCCTGACACCTGGAGCACC CCCCACAGCTACTTCTCCCTGACCTTCTGTGTGCAGGTGCA GGGCAAGAGCAAAAGGGAGAAGAAGGATAGGGTCTTTAC CGACAAGACCAGCGCCACAGTGATCTGCAGGAAGAACGCC AGCATTTCCGTCAGGGCCCAGGACAGGTACTACAGCAGCA GCTGGTCCGAGTGGGCTAGCGTGCCTTGTTCCGGCGGCGG AGGATCTGGCGGAGGCGGAAGTGGCGGAGGGGGCTCTAG AAACCTCCCCGTGGCCACACCCGACCCTGGCATGTTCCCCT GCCTCCACCACAGCCAGAACCTGCTGAGAGCCGTGAGCAA TATGCTGCAGAAGGCCAGGCAAACCCTGGAGTTCTACCCC TGTACCTCCGAGGAGATTGACCATGAGGACATCACAAAGG ACAAAACCAGCACCGTGGAGGCCTGTCTCCCCCTCGAACT GACCAAGAACGAGTCCTGCCTGAACTCCAGGGAGACATCC TTCATCACCAACGGCTCCTGCCTGGCCTCCAGAAAGACCA

GCTTCATGATGGCCCTCTGCCTGAGCAGCATCTACGAGGAC CTCAAGATGTACCAGGTGGAGTTTAAAACAATGAACGCCA AGCTCCTCATGGACCCTAAGAGGCAGATTTTCCTCGACCAG AATATGCTGGCTGTCATTGACGAGCTGATGCAGGCCCTCA ATTTCAACTCCGAGACCGTCCCCCAGAAGTCCTCCCTGGAA GAGCCCGACTTTTACAAGACCAAGATCAAGCTCTGCATCCT GCTGCACGCCTTCAGAATTAGAGCCGTGACCATTGACAGG GTGATGAGCTACCTCAACGCCTCCTGATGACTCGAG 97 human IL-7 GTCGACGCCACCACATCCGCGGCAACGCCTCCTTGGTGTC insert GTCCGCTTCCAATAACCCAGCTTGCGTCCTGC ACACTTGTGGCTTCCGTGCACACATTAACAACTCATGGTTC TAGCTCCCAGTCGCCAAGC GTTGCCAAGGCGTTGAGAGATCATCTGGGAAGTCTTTTACC CAGAATTGCTTTGATTCAG GCCAGCTGGTTTTTCCTGCGGTGATTCGGAAATTCGCGAAT TCCTCTGGTCCTCATCCAG GTGCGCGGGAAGCAGGTGCCCAGGAGAGAGGGGATAATG AAGATTCCATGCTGATGATCC CAAAGATTGAACCTGCAGACCAAGCGCAAAGTAGAAACTG AAAGTACACTGCTGGCGGAT CCTACGGAAGTTATGGAAAAGGCAAAGCGCAGAGCCACGC CGTAGTGTGTGCCGCCCCCC TTGGGATGGATGAAACTGCAGTCGCGGCGTGGGTAAGAGG AACCAGCTGCAGAGATCACC CTGCCCAACACAGACTCGGCAACTCCGCGGAAGACCAGGG TCCTGGGAGTGACTATGGGC GGTGAGAGCTTGCTCCTGCTCCAGTTGCGGTCATCATGACT ACGCCCGCCTCCCGCAGAC CATGTTCCATGTTTCTTTTAGGTATATCTTTGGACTTCCTCC CCTGATCCTTGTTCTGTT GCCAGTAGCATCATCTGATTGTGATATTGAAGGTAAAGAT GGCAAACAATATGAGAGTGT TCTAATGGTCAGCATCGATCAATTATTGGACAGCATGAAA GAAATTGGTAGCAATTGCCT GAATAATGAATTTAACTTTTTTAAAAGACATATCTGTGATG CTAATAAGGAAGGTATGTT TTTATTCCGTGCTGCTCGCAAGTTGAGGCAATTTCTTAAAA TGAATAGCACTGGTGATTT TGATCTCCACTTATTAAAAGTTTCAGAAGGCACAACAATAC TGTTGAACTGCACTGGCCA GGTTAAAGGAAGAAAACCAGCTGCCCTGGGTGAAGCCCAA CCAACAAAGAGTTTGGAAGA AAATAAATCTTTAAAGGAACAGAAAAAACTGAATGACTTG TGTTTCCTAAAGAGACTATT ACAAGAGATAAAAACTTGTTGGAATAAAATTTTGATGGGC ACTAAAGAACACTGAAAAAT ATGGAGTGGCAATATAGAAACACGAACTTTAGCTGCATCC TCCAAGAATCTATCTGCTTA TGCAGTTTTTCAGAGTGGAATGCTTCCTAGAAGTTACTGAA TGCACCATGGTCAAAACGG ATTAGGGCATTTGAGAAATGCATATTGTATTACTAGAAGAT GAATACAAACAATGGAAAC TGAATGCTCCAGTCAACAAACTATTTCTTATATATGTGAAC ATTTATCAATCAGTATAAT TCTGTACTGATTTTTGTAAGACAATCCATGTAAGGTATCAG TTGCAATAATACTTCTCAA ACCTGTTTAAATATTTCAAGACATTAAATCTATGAAGTATA TAATGGTTTCAAAGATTCA AAATTGACATTGCTTTACTGTCAAAATAATTTTATGGCTCA CTATGAATCTATTATACTG TATTAAGAGTGAAAATTGTCTTCTTCTGTGCTGGAGATGTT TTAGAGTTAACAATGATAT ATGGATAATGCCGGTGAGAATAAGAGAGTCATAAACCTTA AGTAAGCAACAGCATAACAA GGTCCAAGATACCTAAAAGAGATTTCAAGAGATTTAATTA ATCATGAATGTGTAACACAG TGCCTTCAATAAATGGTATAGCAAATGTTTTGACATGAAAA AAGGACAATTTCAAAAAAA TAAAATAAAATAAAAATAAATTCACCTAGTCTAAGGATGC TAAACCTTAGTACTGAGTTA CATTGTCATTTATATAGATTATAACTTGTCTAAATAAGTTT GCAATTTGGGAGATATATT TTTAAGATAATAATATATGTTTACCTTTTAATTAATGAAAT ATCTGTATTTAATTTTGAC ACTATATCTGTATATAAAATATTTTCATACAGCATTACAAA TTGCTTACTTTGGAATACA TTTCTCCTTTGATAAAATAAATGAGCTATGTATTAAAAAAA AAAAAAAA 98 human CD70 NCBI GTCGACGCCACCCCAGAGAGGGGCAGGCTGGTCCCCTGA insert Reference CAGGTTGAAGCAAGTAGACGCCCAGGAGCCCCG Sequence: GGAGGGGGCTGCAGTTTCCTTCCTTCCTTCTCGGCAGCGCT NM_001252.4 CCGCGCCCCCATCGCCCCT CCTGCGCTAGCGGAGGTGATCGCCGCGGCGATGCCGGAGG AGGGTTCGGGCTGCTCGGTG CGGCGCAGGCCCTATGGGTGCGTCCTGCGGGCTGCTTTGGT CCCATTGGTCGCGGGCTTG GTGATCTGCCTCGTGGTGTGCATCCAGCGCTTCGCACAGGC TCAGCAGCAGCTGCCGCTC GAGTCACTTGGGTGGGACGTAGCTGAGCTGCAGCTGAATC ACACAGGACCTCAGCAGGAC CCCAGGCTATACTGGCAGGGGGGCCCAGCACTGGGCCGCT CCTTCCTGCATGGACCAGAG CTGGACAAGGGGCAGCTACGTATCCATCGTGATGGCATCT ACATGGTACACATCCAGGTG ACGCTGGCCATCTGCTCCTCCACGACGGCCTCCAGGCACCA CCCCACCACCCTGGCCGTG GGAATCTGCTCTCCCGCCTCCCGTAGCATCAGCCTGCTGCG TCTCAGCTTCCACCAAGGT TGTACCATTGCCTCCCAGCGCCTGACGCCCCTGGCCCGAGG GGACACACTCTGCACCAAC CTCACTGGGACACTTTTGCCTTCCCGAAACACTGATGAGAC CTTCTTTGGAGTGCAGTGG GTGCGCCCCTGACCACTGCTGCTGATTAGGGTTTTTTAAAT TTTATTTTATTTTATTTAA GTTCAAGAGAAAAAGTGTACACACAGGGGCCACCCGGGGT TGGGGTGGGAGTGTGGTGGG GGGTAGTGGTGGCAGGACAAGAGAAGGCATTGAGCTTTTT CTTTCATTTTCCTATTAAAA AATACAAAAATCA 99 NV1 Adenovirus GGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTA E1a AGCGACGGATGTGGCGCAAGTCTATGTTGTAGTAAATTTG Enhancer GGCGTAACCGAGTAAGATTTGGCCATTTTCGCGGGAAAAC Region TGAATAAGAGGAAGTGAAATC Mutant 1 100 NV2 Adenovirus ACAGGAAGTGACATGTTGCAAGTGTGGCGGAACACATGTA E1a AGCGACGGATGTGGCGCAAGTCTATGTTGTAGTAAATTTG Enhancer GGCGTAACCGAGTAAGATTTGGCCATTTTCGCGGGAAAAC Region TGAATAAGAGGAAGTGAAATCT Mutant 2 101 NV3 Adenovirus ACAGGAAGTGACAATTTTCGCGCGGTTTTAGGCGGATGTG E1a GCGCAAGTCTATGTTGTAGTAAATTTGGGCGTAACCGAGT Enhancer AAGATTTGGCCATTTTCGCGGGAAAACTGAATAAGAGGAA Region GTGAAATCT Mutant 3 102 NV4 Adenovirus GGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTA E1a AGCGACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCC Enhancer GGTGTACGGCGGAAGTGTGAATTTTCGCGCGGTTTTAGAC Region GGATGTGGCAGTAAATTTGGGCGTAACCGAGTAAGATTTG Mutant 4 GCCATTTTCGCGGGAAAACTGAATAAGAGGAAGTGAAATC T 103 NV5 Adenovirus GGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTA E1a AGCGACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCC Enhancer GGTGTACGGCGGAAGTGTGAATTTTCGCGCGGTTTTAGAC Region GGATGTGGCAGTAAATTTGGGCGTAACCGAGTAAGATTTG Mutant 5 GCCATTTTCGCGGGAAAACTGAATAAGAGGATGTGAAATC T 104 NV6 Adenovirus GGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTA E1a AGCGACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCC Enhancer GGTGTACGGCGGAAGTGTGAATTTTCGCGCGGTTTTAGAC Region GGATGTGGCAGTAAATTTGGGCGTAACCGAGTAAGATTTG Mutant 6 GCCATTTTCGCGGGAAAACTGAATAGGCGGAAGTGTGATC T 105 NV7 Adenovirus GGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTA E1a AGCGACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCC Enhancer GGTGTACACAGGAAGTGACAATTTTCGCGCGGTTTTAGAC Region GGATGTGGCAGTAAATTTGGGCGTAACCGAGTAAGATTTG Mutant 7 GCCATTTTCGCGGGAAAACTGAATAGGCGGAAGTGTGATC T

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 107 <210> SEQ ID NO 1 <211> LENGTH: 199 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 Met Thr Leu His Pro Ser Pro Ile Thr Cys Glu Phe Leu Phe Ser Thr 1 5 10 15 Ala Leu Ile Ser Pro Lys Met Cys Leu Ser His Leu Glu Asn Met Pro 20 25 30 Leu Ser His Ser Arg Thr Gln Gly Ala Gln Arg Ser Ser Trp Lys Leu 35 40 45 Trp Leu Phe Cys Ser Ile Val Met Leu Leu Phe Leu Cys Ser Phe Ser 50 55 60 Trp Leu Ile Phe Ile Phe Leu Gln Leu Glu Thr Ala Lys Glu Pro Cys 65 70 75 80 Met Ala Lys Phe Gly Pro Leu Pro Ser Lys Trp Gln Met Ala Ser Ser 85 90 95 Glu Pro Pro Cys Val Asn Lys Val Ser Asp Trp Lys Leu Glu Ile Leu 100 105 110 Gln Asn Gly Leu Tyr Leu Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn 115 120 125 Tyr Asn Asp Val Ala Pro Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp 130 135 140 Met Ile Gln Thr Leu Thr Asn Lys Ser Lys Ile Gln Asn Val Gly Gly 145 150 155 160 Thr Tyr Glu Leu His Val Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser 165 170 175 Glu His Gln Val Leu Lys Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu 180 185 190 Ala Asn Pro Gln Phe Ile Ser 195 <210> SEQ ID NO 2 <211> LENGTH: 173 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 2 Met Glu Glu Met Pro Leu Arg Glu Ser Ser Pro Gln Arg Ala Glu Arg 1 5 10 15 Cys Lys Lys Ser Trp Leu Leu Cys Ile Val Ala Leu Leu Leu Met Leu 20 25 30 Leu Cys Ser Leu Gly Thr Leu Ile Tyr Thr Ser Leu Lys Pro Thr Ala 35 40 45 Ile Glu Ser Cys Met Val Lys Phe Glu Leu Ser Ser Ser Lys Trp His 50 55 60 Met Thr Ser Pro Lys Pro His Cys Val Asn Thr Thr Ser Asp Gly Lys 65 70 75 80 Leu Lys Ile Leu Gln Ser Gly Thr Tyr Leu Ile Tyr Gly Gln Val Ile 85 90 95 Pro Val Asp Lys Lys Tyr Ile Lys Asp Asn Ala Pro Phe Val Val Gln 100 105 110 Ile Tyr Lys Lys Asn Asp Val Leu Gln Thr Leu Met Asn Asp Phe Gln 115 120 125 Ile Leu Pro Ile Gly Gly Val Tyr Glu Leu His Ala Gly Asp Asn Ile 130 135 140 Tyr Leu Lys Phe Asn Ser Lys Asp His Ile Gln Lys Thr Asn Thr Tyr 145 150 155 160 Trp Gly Ile Ile Leu Met Pro Asp Leu Pro Phe Ile Ser 165 170 <210> SEQ ID NO 3 <211> LENGTH: 288 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr 1 5 10 15 Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys 20 25 30 Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu 35 40 45 Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile 50 55 60 Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp 65 70 75 80 Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr 85 90 95 Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly 100 105 110 Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg 115 120 125 Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr 130 135 140 Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile 145 150 155 160 Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu 165 170 175 Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp 180 185 190 Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met 195 200 205 Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg 210 215 220 Val Asn Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro 225 230 235 240 Asp Asn Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly 245 250 255 Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg 260 265 270 Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val 275 280 285 <210> SEQ ID NO 4 <211> LENGTH: 233 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala 1 5 10 15 Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe 20 25 30 Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe 35 40 45 Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro 50 55 60 Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser 65 70 75 80 Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro 85 90 95 Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu 100 105 110 Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser 115 120 125 Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly 130 135 140 Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala 145 150 155 160 Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro 165 170 175 Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu 180 185 190 Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu 195 200 205 Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly 210 215 220 Gln Val Tyr Phe Gly Ile Ile Ala Leu 225 230 <210> SEQ ID NO 5 <211> LENGTH: 255 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 5 Met Ile Glu Thr Tyr Ser Gln Pro Ser Pro Arg Ser Val Ala Thr Gly 1 5 10 15 Leu Pro Ala Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Val Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp Phe Val 50 55 60 Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu Val Lys 85 90 95 Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asp Glu Asp Pro Val 100 105 110 Ala His Val Val Ala Asn His Gln Val Glu Glu Gln Leu Glu Trp Leu 115 120 125 Ser Gln Arg Ala Asn Ala Leu Leu Ala Asn Gly Met Asp Leu Lys Asp 130 135 140 Asn Gln Leu Val Val Pro Ala Asp Gly Leu Tyr Leu Val Tyr Ser Gln 145 150 155 160 Val Leu Phe Lys Gly Gln Gly Cys Pro Asp Tyr Val Leu Leu Thr His 165 170 175 Thr Val Ser Arg Phe Ala Ile Ser Tyr Gln Glu Lys Val Asn Leu Leu 180 185 190 Ser Ala Val Lys Ser Pro Cys Pro Lys Asp Thr Pro Glu Gly Ala Glu 195 200 205 Leu Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu 210 215 220 Glu Lys Gly Asp Gln Leu Ser Ala Glu Val Asn Leu Pro Lys Tyr Leu 225 230 235 240 Asp Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu 245 250 255 <210> SEQ ID NO 6 <211> LENGTH: 141 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 6 Met Trp Leu Gln Asn Leu Leu Phe Leu Gly Ile Val Val Tyr Ser Leu 1 5 10 15 Ser Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His 20 25 30 Val Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val 35 40 45 Thr Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys 50 55 60 Lys Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu 65 70 75 80 Arg Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser 85 90 95 Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr 100 105 110 Gln Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu 115 120 125 Thr Asp Ile Pro Phe Glu Cys Lys Lys Pro Gly Gln Lys 130 135 140 <210> SEQ ID NO 7 <211> LENGTH: 302 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 Met Arg Leu Gly Ser Pro Gly Leu Leu Phe Leu Leu Phe Ser Ser Leu 1 5 10 15 Arg Ala Asp Thr Gln Glu Lys Glu Val Arg Ala Met Val Gly Ser Asp 20 25 30 Val Glu Leu Ser Cys Ala Cys Pro Glu Gly Ser Arg Phe Asp Leu Asn 35 40 45 Asp Val Tyr Val Tyr Trp Gln Thr Ser Glu Ser Lys Thr Val Val Thr 50 55 60 Tyr His Ile Pro Gln Asn Ser Ser Leu Glu Asn Val Asp Ser Arg Tyr 65 70 75 80 Arg Asn Arg Ala Leu Met Ser Pro Ala Gly Met Leu Arg Gly Asp Phe 85 90 95 Ser Leu Arg Leu Phe Asn Val Thr Pro Gln Asp Glu Gln Lys Phe His 100 105 110 Cys Leu Val Leu Ser Gln Ser Leu Gly Phe Gln Glu Val Leu Ser Val 115 120 125 Glu Val Thr Leu His Val Ala Ala Asn Phe Ser Val Pro Val Val Ser 130 135 140 Ala Pro His Ser Pro Ser Gln Asp Glu Leu Thr Phe Thr Cys Thr Ser 145 150 155 160 Ile Asn Gly Tyr Pro Arg Pro Asn Val Tyr Trp Ile Asn Lys Thr Asp 165 170 175 Asn Ser Leu Leu Asp Gln Ala Leu Gln Asn Asp Thr Val Phe Leu Asn 180 185 190 Met Arg Gly Leu Tyr Asp Val Val Ser Val Leu Arg Ile Ala Arg Thr 195 200 205 Pro Ser Val Asn Ile Gly Cys Cys Ile Glu Asn Val Leu Leu Gln Gln 210 215 220 Asn Leu Thr Val Gly Ser Gln Thr Gly Asn Asp Ile Gly Glu Arg Asp 225 230 235 240 Lys Ile Thr Glu Asn Pro Val Ser Thr Gly Glu Lys Asn Ala Ala Thr 245 250 255 Trp Ser Ile Leu Ala Val Leu Cys Leu Leu Val Val Val Ala Val Ala 260 265 270 Ile Gly Trp Val Cys Arg Asp Arg Cys Leu Gln His Ser Tyr Ala Gly 275 280 285 Ala Trp Ala Val Ser Pro Glu Thr Glu Leu Thr Gly His Val 290 295 300 <210> SEQ ID NO 8 <211> LENGTH: 254 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Glu Tyr Ala Ser Asp Ala Ser Leu Asp Pro Glu Ala Pro Trp Pro 1 5 10 15 Pro Ala Pro Arg Ala Arg Ala Cys Arg Val Leu Pro Trp Ala Leu Val 20 25 30 Ala Gly Leu Leu Leu Leu Leu Leu Leu Ala Ala Ala Cys Ala Val Phe 35 40 45 Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser 50 55 60 Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp 65 70 75 80 Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val 85 90 95 Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp 100 105 110 Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu 115 120 125 Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe 130 135 140 Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser 145 150 155 160 Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala 165 170 175 Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala 180 185 190 Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala 195 200 205 Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His 210 215 220 Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val 225 230 235 240 Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu 245 250 <210> SEQ ID NO 9 <211> LENGTH: 277 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu 1 5 10 15 Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val 20 25 30 Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro 35 40 45 Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys 50 55 60 Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro 65 70 75 80 Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys 85 90 95 Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly 100 105 110 Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys 115 120 125 Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp 130 135 140 Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn 145 150 155 160 Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro 165 170 175 Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr 180 185 190 Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu 195 200 205 Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val 210 215 220 Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu 225 230 235 240 Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly 245 250 255 Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser 260 265 270 Thr Leu Ala Lys Ile 275 <210> SEQ ID NO 10 <211> LENGTH: 198 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 10 Met Glu Gly Glu Gly Val Gln Pro Leu Asp Glu Asn Leu Glu Asn Gly 1 5 10 15 Ser Arg Pro Arg Phe Lys Trp Lys Lys Thr Leu Arg Leu Val Val Ser 20 25 30 Gly Ile Lys Gly Ala Gly Met Leu Leu Cys Phe Ile Tyr Val Cys Leu 35 40 45 Gln Leu Ser Ser Ser Pro Ala Lys Asp Pro Pro Ile Gln Arg Leu Arg 50 55 60 Gly Ala Val Thr Arg Cys Glu Asp Gly Gln Leu Phe Ile Ser Ser Tyr 65 70 75 80 Lys Asn Glu Tyr Gln Thr Met Glu Val Gln Asn Asn Ser Val Val Ile 85 90 95 Lys Cys Asp Gly Leu Tyr Ile Ile Tyr Leu Lys Gly Ser Phe Phe Gln 100 105 110 Glu Val Lys Ile Asp Leu His Phe Arg Glu Asp His Asn Pro Ile Ser 115 120 125 Ile Pro Met Leu Asn Asp Gly Arg Arg Ile Val Phe Thr Val Val Ala 130 135 140 Ser Leu Ala Phe Lys Asp Lys Val Tyr Leu Thr Val Asn Ala Pro Asp 145 150 155 160 Thr Leu Cys Glu His Leu Gln Ile Asn Asp Gly Glu Leu Ile Val Val 165 170 175 Gln Leu Thr Pro Gly Tyr Cys Ala Pro Glu Gly Ser Tyr His Ser Thr 180 185 190 Val Asn Gln Val Pro Leu 195 <210> SEQ ID NO 11 <211> LENGTH: 261 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly 1 5 10 15 Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val 50 55 60 Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys 85 90 95 Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu 100 105 110 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 115 120 125 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 130 135 140 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 145 150 155 160 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 165 170 175 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 180 185 190 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 195 200 205 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 210 215 220 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 225 230 235 240 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 245 250 255 Gly Leu Leu Lys Leu 260 <210> SEQ ID NO 12 <211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 12 Met Ile Glu Thr Tyr Ser Gln Pro Ser Pro Arg Ser Val Ala Thr Gly 1 5 10 15 Leu Pro Ala Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Val Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp Phe Val 50 55 60 Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu Val Lys 85 90 95 Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asn Ser Phe Glu Met 100 105 110 Gln Arg Gly Asp Glu Asp Pro Gln Ile Ala Ala His Val Val Ser Glu 115 120 125 Ala Asn Ser Asn Ala Ala Ser Val Leu Gln Trp Ala Lys Lys Gly Tyr 130 135 140 Tyr Thr Met Lys Ser Asn Leu Val Met Leu Glu Asn Gly Lys Gln Leu 145 150 155 160 Thr Val Lys Arg Glu Gly Leu Tyr Tyr Val Tyr Thr Gln Val Thr Phe 165 170 175 Cys Ser Asn Arg Glu Pro Ser Ser Gln Arg Pro Phe Ile Val Gly Leu 180 185 190 Trp Leu Lys Pro Ser Ser Gly Ser Glu Arg Ile Leu Leu Lys Ala Ala 195 200 205 Asn Thr His Ser Ser Ser Gln Leu Cys Glu Gln Gln Ser Val His Leu 210 215 220 Gly Gly Val Phe Glu Leu Gln Ala Gly Ala Ser Val Phe Val Asn Val 225 230 235 240 Thr Glu Ala Ser Gln Val Ile His Arg Val Gly Phe Ser Ser Phe Gly 245 250 255 Leu Leu Lys Leu 260 <210> SEQ ID NO 13 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Val Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro <210> SEQ ID NO 14 <211> LENGTH: 195 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 14 Met Pro Glu Glu Gly Arg Pro Cys Pro Trp Val Arg Trp Ser Gly Thr 1 5 10 15 Ala Phe Gln Arg Gln Trp Pro Trp Leu Leu Leu Val Val Phe Ile Thr 20 25 30 Val Phe Cys Cys Trp Phe His Cys Ser Gly Leu Leu Ser Lys Gln Gln 35 40 45 Gln Arg Leu Leu Glu His Pro Glu Pro His Thr Ala Glu Leu Gln Leu 50 55 60 Asn Leu Thr Val Pro Arg Lys Asp Pro Thr Leu Arg Trp Gly Ala Gly 65 70 75 80 Pro Ala Leu Gly Arg Ser Phe Thr His Gly Pro Glu Leu Glu Glu Gly 85 90 95 His Leu Arg Ile His Gln Asp Gly Leu Tyr Arg Leu His Ile Gln Val 100 105 110 Thr Leu Ala Asn Cys Ser Ser Pro Gly Ser Thr Leu Gln His Arg Ala 115 120 125 Thr Leu Ala Val Gly Ile Cys Ser Pro Ala Ala His Gly Ile Ser Leu 130 135 140 Leu Arg Gly Arg Phe Gly Gln Asp Cys Thr Val Ala Leu Gln Arg Leu 145 150 155 160 Thr Tyr Leu Val His Gly Asp Val Leu Cys Thr Asn Leu Thr Leu Pro 165 170 175 Leu Leu Pro Ser Arg Asn Ala Asp Glu Thr Phe Phe Gly Val Gln Trp 180 185 190 Ile Cys Pro 195 <210> SEQ ID NO 15 <211> LENGTH: 153 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu 1 5 10 15 Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu 20 25 30 Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 35 40 45 Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 50 55 60 Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 65 70 75 80 Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 85 90 95 Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 100 105 110 Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 115 120 125 Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 130 135 140 Cys Gln Ser Ile Ile Ser Thr Leu Thr 145 150 <210> SEQ ID NO 16 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His <210> SEQ ID NO 17 <211> LENGTH: 154 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 17 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Ile Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Thr Ser Ser Glu Cys His Ile Lys Asp Lys 20 25 30 Glu Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu 35 40 45 Asp Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn 50 55 60 Phe Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu 65 70 75 80 Asn Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser 85 90 95 Glu Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr 100 105 110 Leu Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys 115 120 125 Lys Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr 130 135 140 Cys Trp Asn Lys Ile Leu Lys Gly Ser Ile 145 150 <210> SEQ ID NO 18 <211> LENGTH: 253 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Trp Pro Pro Gly Ser Ala Ser Gln Pro Pro Pro Ser Pro Ala Ala 1 5 10 15 Ala Thr Gly Leu His Pro Ala Ala Arg Pro Val Ser Leu Gln Cys Arg 20 25 30 Leu Ser Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val 35 40 45 Leu Leu Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro 50 55 60 Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg 65 70 75 80 Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr 85 90 95 Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys 100 105 110 Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu 115 120 125 Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys 130 135 140 Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser 145 150 155 160 Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn 165 170 175 Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn 180 185 190 Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser 195 200 205 Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys 210 215 220 Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala 225 230 235 240 Val Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 245 250 <210> SEQ ID NO 19 <211> LENGTH: 662 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 Met Glu Pro Leu Val Thr Trp Val Val Pro Leu Leu Phe Leu Phe Leu 1 5 10 15 Leu Ser Arg Gln Gly Ala Ala Cys Arg Thr Ser Glu Cys Cys Phe Gln 20 25 30 Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg 35 40 45 Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp 50 55 60 Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys 65 70 75 80 Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg 85 90 95 Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr 100 105 110 Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu 115 120 125 Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly 130 135 140 Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu 145 150 155 160 Thr Pro Asp Asn Gln Val Gly Ala Glu Val Gln Phe Arg His Arg Thr 165 170 175 Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp 180 185 190 Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe 195 200 205 Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys 210 215 220 Trp Ser Ser Pro Val Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln 225 230 235 240 Val Arg Phe Ser Val Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu 245 250 255 Thr Leu Lys Glu Gln Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln 260 265 270 Gly Leu Ala Pro Gly Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met 275 280 285 Leu Ser Cys Pro Cys Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly 290 295 300 Lys Met Pro Tyr Leu Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser 305 310 315 320 Ser Asn Gln Phe Gly Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala 325 330 335 Asp Thr His Thr Glu Pro Val Ala Leu Asn Ile Ser Val Gly Thr Asn 340 345 350 Gly Thr Thr Met Tyr Trp Pro Ala Arg Ala Gln Ser Met Thr Tyr Cys 355 360 365 Ile Glu Trp Gln Pro Val Gly Gln Asp Gly Gly Leu Ala Thr Cys Ser 370 375 380 Leu Thr Ala Pro Gln Asp Pro Asp Pro Ala Gly Met Ala Thr Tyr Ser 385 390 395 400 Trp Ser Arg Glu Ser Gly Ala Met Gly Gln Glu Lys Cys Tyr Tyr Ile 405 410 415 Thr Ile Phe Ala Ser Ala His Pro Glu Lys Leu Thr Leu Trp Ser Thr 420 425 430 Val Leu Ser Thr Tyr His Phe Gly Gly Asn Ala Ser Ala Ala Gly Thr 435 440 445 Pro His His Val Ser Val Lys Asn His Ser Leu Asp Ser Val Ser Val 450 455 460 Asp Trp Ala Pro Ser Leu Leu Ser Thr Cys Pro Gly Val Leu Lys Glu 465 470 475 480 Tyr Val Val Arg Cys Arg Asp Glu Asp Ser Lys Gln Val Ser Glu His 485 490 495 Pro Val Gln Pro Thr Glu Thr Gln Val Thr Leu Ser Gly Leu Arg Ala 500 505 510 Gly Val Ala Tyr Thr Val Gln Val Arg Ala Asp Thr Ala Trp Leu Arg 515 520 525 Gly Val Trp Ser Gln Pro Gln Arg Phe Ser Ile Glu Val Gln Val Ser 530 535 540 Asp Trp Leu Ile Phe Phe Ala Ser Leu Gly Ser Phe Leu Ser Ile Leu 545 550 555 560 Leu Val Gly Val Leu Gly Tyr Leu Gly Leu Asn Arg Ala Ala Arg His 565 570 575 Leu Cys Pro Pro Leu Pro Thr Pro Cys Ala Ser Ser Ala Ile Glu Phe 580 585 590 Pro Gly Gly Lys Glu Thr Trp Gln Trp Ile Asn Pro Val Asp Phe Gln 595 600 605 Glu Glu Ala Ser Leu Gln Glu Ala Leu Val Val Glu Met Ser Trp Asp 610 615 620 Lys Gly Glu Arg Thr Glu Pro Leu Glu Lys Thr Glu Leu Pro Glu Gly 625 630 635 640 Ala Pro Glu Leu Ala Leu Asp Thr Glu Leu Ser Leu Glu Asp Gly Asp 645 650 655 Arg Cys Lys Ala Lys Met 660 <210> SEQ ID NO 20 <211> LENGTH: 543 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 20 Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu 1 5 10 15 Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys 65 70 75 80 Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr 85 90 95 Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp 100 105 110 Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys 115 120 125 Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln 130 135 140 Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro 145 150 155 160 Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys 165 170 175 Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln 180 185 190 Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu 195 200 205 Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser 210 215 220 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 225 230 235 240 Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro 245 250 255 Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val 260 265 270 Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys 275 280 285 Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln 290 295 300 Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn 305 310 315 320 Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser Gly 325 330 335 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Val 340 345 350 Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu 355 360 365 Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys Leu Lys 370 375 380 His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile Thr Arg 385 390 395 400 Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu His Lys 405 410 415 Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly 420 425 430 Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu Cys Leu 435 440 445 Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala 450 455 460 Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile Leu Asp 465 470 475 480 Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu Asn His 485 490 495 Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala Asp Pro 500 505 510 Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe Ser Thr 515 520 525 Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser Ala 530 535 540 <210> SEQ ID NO 21 <211> LENGTH: 162 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Met Arg Ile Ser Lys Pro His Leu Arg Ser Ile Ser Ile Gln Cys Tyr 1 5 10 15 Leu Cys Leu Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His 20 25 30 Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys Thr Glu Ala 35 40 45 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 50 55 60 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 65 70 75 80 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 85 90 95 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 100 105 110 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 115 120 125 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 130 135 140 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 145 150 155 160 Thr Ser <210> SEQ ID NO 22 <211> LENGTH: 357 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 22 Met Lys Ile Leu Lys Pro Tyr Met Arg Asn Thr Ser Ile Ser Cys Tyr 1 5 10 15 Leu Cys Phe Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His 20 25 30 Val Phe Ile Leu Gly Cys Val Ser Val Gly Leu Pro Lys Thr Glu Ala 35 40 45 Asn Trp Ile Asp Val Arg Tyr Asp Leu Glu Lys Ile Glu Ser Leu Ile 50 55 60 Gln Ser Ile His Ile Asp Thr Thr Leu Tyr Thr Asp Ser Asp Phe His 65 70 75 80 Pro Ser Cys Lys Val Thr Ala Met Asn Cys Phe Leu Leu Glu Leu Gln 85 90 95 Val Ile Leu His Glu Tyr Ser Asn Met Thr Leu Asn Glu Thr Val Arg 100 105 110 Asn Val Leu Tyr Leu Ala Asn Ser Thr Leu Ser Ser Asn Lys Asn Val 115 120 125 Ala Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Thr Phe 130 135 140 Thr Glu Phe Leu Gln Ser Phe Ile Arg Ile Val Gln Met Phe Ile Asn 145 150 155 160 Thr Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly 165 170 175 Asp Val Glu Glu Asn Pro Gly Pro Gly Thr Thr Cys Pro Pro Pro Val 180 185 190 Ser Ile Glu His Ala Asp Ile Arg Val Lys Asn Tyr Ser Val Asn Ser 195 200 205 Arg Glu Arg Tyr Val Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr 210 215 220 Ser Thr Leu Ile Glu Cys Val Ile Asn Lys Asn Thr Asn Val Ala His 225 230 235 240 Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ser Leu Ala His 245 250 255 Tyr Ser Pro Val Pro Thr Val Val Thr Pro Lys Val Thr Ser Gln Pro 260 265 270 Glu Ser Pro Ser Pro Ser Ala Lys Glu Pro Glu Ala Phe Ser Pro Lys 275 280 285 Ser Asp Thr Ala Met Thr Thr Glu Thr Ala Ile Met Pro Gly Ser Arg 290 295 300 Leu Thr Pro Ser Gln Thr Thr Ser Ala Gly Thr Thr Gly Thr Gly Ser 305 310 315 320 His Lys Ser Ser Arg Ala Pro Ser Leu Ala Ala Thr Met Thr Leu Glu 325 330 335 Pro Thr Ala Ser Thr Ser Leu Arg Ile Thr Glu Ile Ser Pro His Ser 340 345 350 Ser Lys Met Thr Lys 355 <210> SEQ ID NO 23 <211> LENGTH: 578 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg 1 5 10 15 Leu Gly Ser Asp Ala His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val 20 25 30 Trp Phe Glu Ala Glu Phe Phe His His Ile Leu His Trp Thr Pro Ile 35 40 45 Pro Asn Gln Ser Glu Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr 50 55 60 Gly Ile Glu Ser Trp Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser 65 70 75 80 Tyr Asp Leu Thr Ala Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr 85 90 95 Arg Ala Arg Val Arg Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr 100 105 110 Val Thr Asn Thr Arg Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly 115 120 125 Ser Val Asn Leu Glu Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln 130 135 140 Leu Pro Arg Pro Lys Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile 145 150 155 160 Phe Ser His Phe Arg Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly 165 170 175 Asn Phe Thr Phe Thr His Lys Lys Val Lys His Glu Asn Phe Ser Leu 180 185 190 Leu Thr Ser Gly Glu Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser 195 200 205 Val Ala Ser Arg Ser Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile 210 215 220 Ser Leu Thr Arg Gln Tyr Phe Thr Val Thr Asn Val Ile Ile Phe Phe 225 230 235 240 Ala Phe Val Leu Leu Leu Ser Gly Ala Leu Ala Tyr Cys Leu Ala Leu 245 250 255 Gln Leu Tyr Val Arg Arg Arg Lys Lys Leu Pro Ser Val Leu Leu Phe 260 265 270 Lys Lys Pro Ser Pro Phe Ile Phe Ile Ser Gln Arg Pro Ser Pro Glu 275 280 285 Thr Gln Asp Thr Ile His Pro Leu Asp Glu Glu Ala Phe Leu Lys Val 290 295 300 Ser Pro Glu Leu Lys Asn Leu Asp Leu His Gly Ser Thr Asp Ser Gly 305 310 315 320 Phe Gly Ser Thr Lys Pro Ser Leu Gln Thr Glu Glu Pro Gln Phe Leu 325 330 335 Leu Pro Asp Pro His Pro Gln Ala Asp Arg Thr Leu Gly Asn Arg Glu 340 345 350 Pro Pro Val Leu Gly Asp Ser Cys Ser Ser Gly Ser Ser Asn Ser Thr 355 360 365 Asp Ser Gly Ile Cys Leu Gln Glu Pro Ser Leu Ser Pro Ser Thr Gly 370 375 380 Pro Thr Trp Glu Gln Gln Val Gly Ser Asn Ser Arg Gly Gln Asp Asp 385 390 395 400 Ser Gly Ile Asp Leu Val Gln Asn Ser Glu Gly Arg Ala Gly Asp Thr 405 410 415 Gln Gly Gly Ser Ala Leu Gly His His Ser Pro Pro Glu Pro Glu Val 420 425 430 Pro Gly Glu Glu Asp Pro Ala Ala Val Ala Phe Gln Gly Tyr Leu Arg 435 440 445 Gln Thr Arg Cys Ala Glu Glu Lys Ala Thr Lys Thr Gly Cys Leu Glu 450 455 460 Glu Glu Ser Pro Leu Thr Asp Gly Leu Gly Pro Lys Phe Gly Arg Cys 465 470 475 480 Leu Val Asp Glu Ala Gly Leu His Pro Pro Ala Leu Ala Lys Gly Tyr 485 490 495 Leu Lys Gln Asp Pro Leu Glu Met Thr Leu Ala Ser Ser Gly Ala Pro 500 505 510 Thr Gly Gln Trp Asn Gln Pro Thr Glu Glu Trp Ser Leu Leu Ala Leu 515 520 525 Ser Ser Cys Ser Asp Leu Gly Ile Ser Asp Trp Ser Phe Ala His Asp 530 535 540 Leu Ala Pro Leu Gly Cys Val Ala Ala Pro Gly Gly Leu Leu Gly Ser 545 550 555 560 Phe Asn Ser Asp Leu Val Thr Leu Pro Leu Ile Ser Ser Leu Gln Ser 565 570 575 Ser Glu <210> SEQ ID NO 24 <211> LENGTH: 479 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 24 Met Leu Ser Arg Leu Leu Pro Phe Leu Val Thr Ile Ser Ser Leu Ser 1 5 10 15 Leu Glu Phe Ile Ala Tyr Gly Thr Glu Leu Pro Ser Pro Ser Tyr Val 20 25 30 Trp Phe Glu Ala Arg Phe Phe Gln His Ile Leu His Trp Lys Pro Ile 35 40 45 Pro Asn Gln Ser Glu Ser Thr Tyr Tyr Glu Val Ala Leu Lys Gln Tyr 50 55 60 Gly Asn Ser Thr Trp Asn Asp Ile His Ile Cys Arg Lys Ala Gln Ala 65 70 75 80 Leu Ser Cys Asp Leu Thr Thr Phe Thr Leu Asp Leu Tyr His Arg Ser 85 90 95 Tyr Gly Tyr Arg Ala Arg Val Arg Ala Val Asp Asn Ser Gln Tyr Ser 100 105 110 Asn Trp Thr Thr Thr Glu Thr Arg Phe Thr Val Asp Glu Val Ile Leu 115 120 125 Thr Val Asp Ser Val Thr Leu Lys Ala Met Asp Gly Ile Ile Tyr Gly 130 135 140 Thr Ile His Pro Pro Arg Pro Thr Ile Thr Pro Ala Gly Asp Glu Tyr 145 150 155 160 Glu Gln Val Phe Lys Asp Leu Arg Val Tyr Lys Ile Ser Ile Arg Lys 165 170 175 Phe Ser Glu Leu Lys Asn Ala Thr Lys Arg Val Lys Gln Glu Thr Phe 180 185 190 Thr Leu Thr Val Pro Ile Gly Val Arg Lys Phe Cys Val Lys Val Leu 195 200 205 Pro Arg Leu Glu Ser Arg Ile Asn Lys Ala Glu Trp Ser Glu Glu Gln 210 215 220 Cys Leu Leu Ile Thr Thr Glu Gln Tyr Phe Thr Val Thr Asn Leu Ser 225 230 235 240 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 245 250 255 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 260 265 270 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 275 280 285 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 290 295 300 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 305 310 315 320 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 325 330 335 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 340 345 350 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 370 375 380 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 385 390 395 400 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 405 410 415 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 420 425 430 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 435 440 445 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 450 455 460 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 465 470 475 <210> SEQ ID NO 25 <211> LENGTH: 636 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 Met Arg Gly Gly Arg Gly Ala Pro Phe Trp Leu Trp Pro Leu Pro Lys 1 5 10 15 Leu Ala Leu Leu Pro Leu Leu Trp Val Leu Phe Gln Arg Thr Arg Pro 20 25 30 Gln Gly Ser Ala Gly Pro Leu Gln Cys Tyr Gly Val Gly Pro Leu Gly 35 40 45 Asp Leu Asn Cys Ser Trp Glu Pro Leu Gly Asp Leu Gly Ala Pro Ser 50 55 60 Glu Leu His Leu Gln Ser Gln Lys Tyr Arg Ser Asn Lys Thr Gln Thr 65 70 75 80 Val Ala Val Ala Ala Gly Arg Ser Trp Val Ala Ile Pro Arg Glu Gln 85 90 95 Leu Thr Met Ser Asp Lys Leu Leu Val Trp Gly Thr Lys Ala Gly Gln 100 105 110 Pro Leu Trp Pro Pro Val Phe Val Asn Leu Glu Thr Gln Met Lys Pro 115 120 125 Asn Ala Pro Arg Leu Gly Pro Asp Val Asp Phe Ser Glu Asp Asp Pro 130 135 140 Leu Glu Ala Thr Val His Trp Ala Pro Pro Thr Trp Pro Ser His Lys 145 150 155 160 Val Leu Ile Cys Gln Phe His Tyr Arg Arg Cys Gln Glu Ala Ala Trp 165 170 175 Thr Leu Leu Glu Pro Glu Leu Lys Thr Ile Pro Leu Thr Pro Val Glu 180 185 190 Ile Gln Asp Leu Glu Leu Ala Thr Gly Tyr Lys Val Tyr Gly Arg Cys 195 200 205 Arg Met Glu Lys Glu Glu Asp Leu Trp Gly Glu Trp Ser Pro Ile Leu 210 215 220 Ser Phe Gln Thr Pro Pro Ser Ala Pro Lys Asp Val Trp Val Ser Gly 225 230 235 240 Asn Leu Cys Gly Thr Pro Gly Gly Glu Glu Pro Leu Leu Leu Trp Lys 245 250 255 Ala Pro Gly Pro Cys Val Gln Val Ser Tyr Lys Val Trp Phe Trp Val 260 265 270 Gly Gly Arg Glu Leu Ser Pro Glu Gly Ile Thr Cys Cys Cys Ser Leu 275 280 285 Ile Pro Ser Gly Ala Glu Trp Ala Arg Val Ser Ala Val Asn Ala Thr 290 295 300 Ser Trp Glu Pro Leu Thr Asn Leu Ser Leu Val Cys Leu Asp Ser Ala 305 310 315 320 Ser Ala Pro Arg Ser Val Ala Val Ser Ser Ile Ala Gly Ser Thr Glu 325 330 335 Leu Leu Val Thr Trp Gln Pro Gly Pro Gly Glu Pro Leu Glu His Val 340 345 350 Val Asp Trp Ala Arg Asp Gly Asp Pro Leu Glu Lys Leu Asn Trp Val 355 360 365 Arg Leu Pro Pro Gly Asn Leu Ser Ala Leu Leu Pro Gly Asn Phe Thr 370 375 380 Val Gly Val Pro Tyr Arg Ile Thr Val Thr Ala Val Ser Ala Ser Gly 385 390 395 400 Leu Ala Ser Ala Ser Ser Val Trp Gly Phe Arg Glu Glu Leu Ala Pro 405 410 415 Leu Val Gly Pro Thr Leu Trp Arg Leu Gln Asp Ala Pro Pro Gly Thr 420 425 430 Pro Ala Ile Ala Trp Gly Glu Val Pro Arg His Gln Leu Arg Gly His 435 440 445 Leu Thr His Tyr Thr Leu Cys Ala Gln Ser Gly Thr Ser Pro Ser Val 450 455 460 Cys Met Asn Val Ser Gly Asn Thr Gln Ser Val Thr Leu Pro Asp Leu 465 470 475 480 Pro Trp Gly Pro Cys Glu Leu Trp Val Thr Ala Ser Thr Ile Ala Gly 485 490 495 Gln Gly Pro Pro Gly Pro Ile Leu Arg Leu His Leu Pro Asp Asn Thr 500 505 510 Leu Arg Trp Lys Val Leu Pro Gly Ile Leu Phe Leu Trp Gly Leu Phe 515 520 525 Leu Leu Gly Cys Gly Leu Ser Leu Ala Thr Ser Gly Arg Cys Tyr His 530 535 540 Leu Arg His Lys Val Leu Pro Arg Trp Val Trp Glu Lys Val Pro Asp 545 550 555 560 Pro Ala Asn Ser Ser Ser Gly Gln Pro His Met Glu Gln Val Pro Glu 565 570 575 Ala Gln Pro Leu Gly Asp Leu Pro Ile Leu Glu Val Glu Glu Met Glu 580 585 590 Pro Pro Pro Val Met Glu Ser Ser Gln Pro Ala Gln Ala Thr Ala Pro 595 600 605 Leu Asp Ser Gly Tyr Glu Lys His Phe Leu Pro Thr Pro Glu Glu Leu 610 615 620 Gly Leu Leu Gly Pro Pro Arg Pro Gln Val Leu Ala 625 630 635 <210> SEQ ID NO 26 <211> LENGTH: 81 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu 1 5 10 15 Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln 20 25 30 Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe 35 40 45 Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val 50 55 60 Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly Arg Phe 65 70 75 80 Asn <210> SEQ ID NO 27 <211> LENGTH: 155 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Met Thr Pro Gly Lys Thr Ser Leu Val Ser Leu Leu Leu Leu Leu Ser 1 5 10 15 Leu Glu Ala Ile Val Lys Ala Gly Ile Thr Ile Pro Arg Asn Pro Gly 20 25 30 Cys Pro Asn Ser Glu Asp Lys Asn Phe Pro Arg Thr Val Met Val Asn 35 40 45 Leu Asn Ile His Asn Arg Asn Thr Asn Thr Asn Pro Lys Arg Ser Ser 50 55 60 Asp Tyr Tyr Asn Arg Ser Thr Ser Pro Trp Asn Leu His Arg Asn Glu 65 70 75 80 Asp Pro Glu Arg Tyr Pro Ser Val Ile Trp Glu Ala Lys Cys Arg His 85 90 95 Leu Gly Cys Ile Asn Ala Asp Gly Asn Val Asp Tyr His Met Asn Ser 100 105 110 Val Pro Ile Gln Gln Glu Ile Leu Val Leu Arg Arg Glu Pro Pro His 115 120 125 Cys Pro Asn Ser Phe Arg Leu Glu Lys Ile Leu Val Ser Val Gly Cys 130 135 140 Thr Cys Val Thr Pro Ile Val His His Val Ala 145 150 155 <210> SEQ ID NO 28 <211> LENGTH: 270 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> SEQ ID NO 29 <211> LENGTH: 270 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> SEQ ID NO 30 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser 115 120 125 Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu 130 135 140 Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser 145 150 155 160 Val Glu Leu His Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe 165 170 175 Val Leu His Asn Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr 180 185 190 Asp Pro Gly Val Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile 195 200 205 Lys Val Asp Ser Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys 210 215 220 Leu Ser Glu Thr 225 <210> SEQ ID NO 31 <211> LENGTH: 144 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Asn Lys 20 25 30 Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly 35 40 45 Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys 50 55 60 Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His 65 70 75 80 Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn 85 90 95 Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val 100 105 110 Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser 115 120 125 Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 130 135 140 <210> SEQ ID NO 32 <211> LENGTH: 264 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr Tyr Asn Asp Gln Ser Ile 115 120 125 Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu Ile Tyr Val Glu Asp Leu 130 135 140 Lys Lys Asp Glu Lys Lys Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser 145 150 155 160 Gln His Pro Ser Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu 165 170 175 Met Val Thr Leu Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn 180 185 190 Lys Glu His Ser Val Glu Leu His Lys Cys Glu Lys Pro Leu Pro Asp 195 200 205 Gln Ala Phe Phe Val Leu His Asn Met His Ser Asn Cys Val Ser Phe 210 215 220 Glu Cys Lys Thr Asp Pro Gly Val Phe Ile Gly Val Lys Asp Asn His 225 230 235 240 Leu Ala Leu Ile Lys Val Asp Ser Ser Glu Asn Leu Cys Thr Glu Asn 245 250 255 Ile Leu Phe Lys Leu Ser Glu Thr 260 <210> SEQ ID NO 33 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Ile Ser Pro Ile Thr Glu Tyr 65 70 75 80 Leu Ala Ser Leu Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu 85 90 95 Glu Asp Glu Ser Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu 100 105 110 Lys Lys Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser 115 120 125 Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu 130 135 140 Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser 145 150 155 160 Val Glu Leu His Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe 165 170 175 Val Leu His Asn Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr 180 185 190 Asp Pro Gly Val Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile 195 200 205 Lys Val Asp Ser Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys 210 215 220 Leu Ser Glu Thr 225 <210> SEQ ID NO 34 <211> LENGTH: 166 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Met Lys Tyr Thr Ser Tyr Ile Leu Ala Phe Gln Leu Cys Ile Val Leu 1 5 10 15 Gly Ser Leu Gly Cys Tyr Cys Gln Asp Pro Tyr Val Lys Glu Ala Glu 20 25 30 Asn Leu Lys Lys Tyr Phe Asn Ala Gly His Ser Asp Val Ala Asp Asn 35 40 45 Gly Thr Leu Phe Leu Gly Ile Leu Lys Asn Trp Lys Glu Glu Ser Asp 50 55 60 Arg Lys Ile Met Gln Ser Gln Ile Val Ser Phe Tyr Phe Lys Leu Phe 65 70 75 80 Lys Asn Phe Lys Asp Asp Gln Ser Ile Gln Lys Ser Val Glu Thr Ile 85 90 95 Lys Glu Asp Met Asn Val Lys Phe Phe Asn Ser Asn Lys Lys Lys Arg 100 105 110 Asp Asp Phe Glu Lys Leu Thr Asn Tyr Ser Val Thr Asp Leu Asn Val 115 120 125 Gln Arg Lys Ala Ile His Glu Leu Ile Gln Val Met Ala Glu Leu Ser 130 135 140 Pro Ala Ala Lys Thr Gly Lys Arg Lys Arg Ser Gln Met Leu Phe Arg 145 150 155 160 Gly Arg Arg Ala Ser Gln 165 <210> SEQ ID NO 35 <211> LENGTH: 495 <212> TYPE: PRT <213> ORGANISM: Salmonella enterica <400> SEQUENCE: 35 Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn 1 5 10 15 Asn Leu Asn Lys Ser Gln Ser Ala Leu Gly Thr Ala Ile Glu Arg Leu 20 25 30 Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45 Ala Ile Ala Asn Arg Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 65 70 75 80 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala 85 90 95 Val Gln Ser Ala Asn Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile 100 105 110 Gln Ala Glu Ile Thr Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly 115 120 125 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu 130 135 140 Thr Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu 145 150 155 160 Lys Gln Ile Asn Ser Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln 165 170 175 Gln Lys Tyr Lys Val Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala 180 185 190 Asp Thr Thr Ile Ala Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr 195 200 205 Gly Leu Gly Gly Thr Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp 210 215 220 Asp Thr Thr Gly Lys Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Thr 225 230 235 240 Gly Lys Asp Gly Tyr Tyr Glu Val Ser Val Asp Lys Thr Asn Gly Glu 245 250 255 Val Thr Leu Ala Gly Gly Ala Thr Ser Pro Leu Thr Gly Gly Leu Pro 260 265 270 Ala Thr Ala Thr Glu Asp Val Lys Asn Val Gln Val Ala Asn Ala Asp 275 280 285 Leu Thr Glu Ala Lys Ala Ala Leu Thr Ala Ala Gly Val Thr Gly Thr 290 295 300 Ala Ser Val Val Lys Met Ser Tyr Thr Asp Asn Asn Gly Lys Thr Ile 305 310 315 320 Asp Gly Gly Leu Ala Val Lys Val Gly Asp Asp Tyr Tyr Ser Ala Thr 325 330 335 Gln Asn Lys Asp Gly Ser Ile Ser Ile Asn Thr Thr Lys Tyr Thr Ala 340 345 350 Asp Asp Gly Thr Ser Lys Thr Ala Leu Asn Lys Leu Gly Gly Ala Asp 355 360 365 Gly Lys Thr Glu Val Val Ser Ile Gly Gly Lys Thr Tyr Ala Ala Ser 370 375 380 Lys Ala Glu Gly His Asn Phe Lys Ala Gln Pro Asp Leu Ala Glu Ala 385 390 395 400 Ala Ala Thr Thr Thr Glu Asn Pro Leu Gln Lys Ile Asp Ala Ala Leu 405 410 415 Ala Gln Val Asp Thr Leu Arg Ser Asp Leu Gly Ala Val Gln Asn Arg 420 425 430 Phe Asn Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Asn Asn Leu Thr 435 440 445 Ser Ala Arg Ser Arg Ile Glu Asp Ser Asp Tyr Ala Thr Glu Val Ser 450 455 460 Asn Met Ser Arg Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 465 470 475 480 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 485 490 495 <210> SEQ ID NO 36 <211> LENGTH: 507 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 36 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Thr Thr Leu Ser 20 25 30 Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn 65 70 75 80 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Gly 130 135 140 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Glu Ala Lys 145 150 155 160 Leu Gln Glu Ser Gly Pro Val Leu Val Lys Pro Gly Ala Ser Val Lys 165 170 175 Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met Asn 180 185 190 Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Val Ile 195 200 205 Asn Pro Tyr Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys 210 215 220 Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu 225 230 235 240 Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr 245 250 255 Tyr Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Ile Thr Val 260 265 270 Ser Thr Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys 275 280 285 Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro 290 295 300 Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr 305 310 315 320 Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser 325 330 335 Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His 340 345 350 Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile 355 360 365 Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn 370 375 380 Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys 385 390 395 400 Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu 405 410 415 Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe 420 425 430 Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu 435 440 445 Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr 450 455 460 Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg 465 470 475 480 Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His 485 490 495 Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 500 505 <210> SEQ ID NO 37 <211> LENGTH: 955 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 37 tatcaccctt gctaatcact cctcacagtg acctcaagtc ctgcaggcat gtacagcatg 60 cagctcgcat cctgtgtcac attgacactt gtgctccttg tcaacagcgc acccacttca 120 agctccactt caagctctac agcggaagca cagcagcagc agcagcagca gcagcagcag 180 cagcagcacc tggagcagct gttgatggac ctacaggagc tcctgagcag gatggagaat 240 tacaggaacc tgaaactccc caggatgctc accttcaaat tttacttgcc caagcaggcc 300 acagaattga aagatcttca gtgcctagaa gatgaacttg gacctctgcg gcatgttctg 360 gatttgactc aaagcaaaag ctttcaattg gaagatgctg agaatttcat cagcaatatc 420 agagtaactg ttgtaaaact aaagggctct gacaacacat ttgagtgcca attcgatgat 480 gagtcagcaa ctgtggtgga ctttctgagg agatggatag ccttctgtca aagcatcatc 540 tcaacaagcc ctcaataact atgtacctcc tgcttacaac acataaggct ctctatttat 600 ttaaatattt aactttaatt tatttttgga tgtattgttt actatctttt gtaactacta 660 gtcttcagat gataaatatg gatctttaaa gattcttttt gtaagcccca agggctcaaa 720 aatgttttaa actatttatc tgaaattatt tattatattg aattgttaaa tatcatgtgt 780 aggtagactc attaataaaa gtatttagat gattcaaata taaataagct cagatgtctg 840 tcatttttag gacagcacaa agtaagcgct aaaataactt ctcagttatt cctgtgaact 900 ctatgttaat cagtgttttc aagaaataaa gctctcctct aaaaaaaaaa aaaaa 955 <210> SEQ ID NO 38 <211> LENGTH: 169 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 38 Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu 1 5 10 15 Leu Val Asn Ser Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser Thr Ala 20 25 30 Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Leu 35 40 45 Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser Arg Met Glu Asn 50 55 60 Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe Lys Phe Tyr Leu 65 70 75 80 Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu Asp Glu 85 90 95 Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln Ser Lys Ser Phe 100 105 110 Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile Arg Val Thr Val 115 120 125 Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe Asp Asp 130 135 140 Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp Ile Ala Phe Cys 145 150 155 160 Gln Ser Ile Ile Ser Thr Ser Pro Gln 165 <210> SEQ ID NO 39 <211> LENGTH: 525 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 39 agcccagcaa gacctcagcc atgagacttc tcctcctgac tttcctggga gtctgctgcc 60 tcaccccatg ggttgtggaa ggtgtgggga ctgaagtcct agaagagagt agctgtgtga 120 acttacaaac ccagcggctg ccagttcaaa aaatcaagac ctatatcatc tgggaggggg 180 ccatgagagc tgtaattttt gtcaccaaac gaggactaaa aatttgtgct gatccagaag 240 ccaaatgggt gaaagcagcg atcaagactg tggatggcag ggccagtacc agaaagaaca 300 tggctgaaac tgttcccaca ggagcccaga ggtccaccag cacagcgata accctgactg 360 ggtaacagcc tccaggacaa tgtttcctca ctcgttaagc agctcatctc agttcccaaa 420 cccattgcac aaatacttat ttttattttt aacgacattc acattcattt caaatgttat 480 aagtaataaa tatttattat tgatgaaaaa aaaaaaaaaa aaaaa 525 <210> SEQ ID NO 40 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 40 Met Arg Leu Leu Leu Leu Thr Phe Leu Gly Val Cys Cys Leu Thr Pro 1 5 10 15 Trp Val Val Glu Gly Val Gly Thr Glu Val Leu Glu Glu Ser Ser Cys 20 25 30 Val Asn Leu Gln Thr Gln Arg Leu Pro Val Gln Lys Ile Lys Thr Tyr 35 40 45 Ile Ile Trp Glu Gly Ala Met Arg Ala Val Ile Phe Val Thr Lys Arg 50 55 60 Gly Leu Lys Ile Cys Ala Asp Pro Glu Ala Lys Trp Val Lys Ala Ala 65 70 75 80 Ile Lys Thr Val Asp Gly Arg Ala Ser Thr Arg Lys Asn Met Ala Glu 85 90 95 Thr Val Pro Thr Gly Ala Gln Arg Ser Thr Ser Thr Ala Ile Thr Leu 100 105 110 Thr Gly <210> SEQ ID NO 41 <211> LENGTH: 1028 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 41 gagacgtgca ctgaccgacc gtggtaatgg accagcacac acttgatgtg gaggataccg 60 cggatgccag acatccagca ggtacttcgt gcccctcgga tgcggcgctc ctcagagata 120 ccgggctcct cgcggacgct gcgctcctct cagatactgt gcgccccaca aatgccgcgc 180 tccccacgga tgctgcctac cctgcggtta atgttcggga tcgcgaggcc gcgtggccgc 240 ctgcactgaa cttctgttcc cgccacccaa agctctatgg cctagtcgct ttggttttgc 300 tgcttctgat cgccgcctgt gttcctatct tcacccgcac cgagcctcgg ccagcgctca 360 caatcaccac ctcgcccaac ctgggtaccc gagagaataa tgcagaccag gtcacccctg 420 tttcccacat tggctgcccc aacactacac aacagggctc tcctgtgttc gccaagctac 480 tggctaaaaa ccaagcatcg ttgtgcaata caactctgaa ctggcacagc caagatggag 540 ctgggagctc atacctatct caaggtctga ggtacgaaga agacaaaaag gagttggtgg 600 tagacagtcc cgggctctac tacgtatttt tggaactgaa gctcagtcca acattcacaa 660 acacaggcca caaggtgcag ggctgggtct ctcttgtttt gcaagcaaag cctcaggtag 720 atgactttga caacttggcc ctgacagtgg aactgttccc ttgctccatg gagaacaagt 780 tagtggaccg ttcctggagt caactgttgc tcctgaaggc tggccaccgc ctcagtgtgg 840 gtctgagggc ttatctgcat ggagcccagg atgcatacag agactgggag ctgtcttatc 900 ccaacaccac cagctttgga ctctttcttg tgaaacccga caacccatgg gaatgagaac 960 tatccttctt gtgactccta gttgctaagt cctcaagctg ctatgtttta tggggtctga 1020 gcaggggt 1028 <210> SEQ ID NO 42 <211> LENGTH: 309 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 42 Met Asp Gln His Thr Leu Asp Val Glu Asp Thr Ala Asp Ala Arg His 1 5 10 15 Pro Ala Gly Thr Ser Cys Pro Ser Asp Ala Ala Leu Leu Arg Asp Thr 20 25 30 Gly Leu Leu Ala Asp Ala Ala Leu Leu Ser Asp Thr Val Arg Pro Thr 35 40 45 Asn Ala Ala Leu Pro Thr Asp Ala Ala Tyr Pro Ala Val Asn Val Arg 50 55 60 Asp Arg Glu Ala Ala Trp Pro Pro Ala Leu Asn Phe Cys Ser Arg His 65 70 75 80 Pro Lys Leu Tyr Gly Leu Val Ala Leu Val Leu Leu Leu Leu Ile Ala 85 90 95 Ala Cys Val Pro Ile Phe Thr Arg Thr Glu Pro Arg Pro Ala Leu Thr 100 105 110 Ile Thr Thr Ser Pro Asn Leu Gly Thr Arg Glu Asn Asn Ala Asp Gln 115 120 125 Val Thr Pro Val Ser His Ile Gly Cys Pro Asn Thr Thr Gln Gln Gly 130 135 140 Ser Pro Val Phe Ala Lys Leu Leu Ala Lys Asn Gln Ala Ser Leu Cys 145 150 155 160 Asn Thr Thr Leu Asn Trp His Ser Gln Asp Gly Ala Gly Ser Ser Tyr 165 170 175 Leu Ser Gln Gly Leu Arg Tyr Glu Glu Asp Lys Lys Glu Leu Val Val 180 185 190 Asp Ser Pro Gly Leu Tyr Tyr Val Phe Leu Glu Leu Lys Leu Ser Pro 195 200 205 Thr Phe Thr Asn Thr Gly His Lys Val Gln Gly Trp Val Ser Leu Val 210 215 220 Leu Gln Ala Lys Pro Gln Val Asp Asp Phe Asp Asn Leu Ala Leu Thr 225 230 235 240 Val Glu Leu Phe Pro Cys Ser Met Glu Asn Lys Leu Val Asp Arg Ser 245 250 255 Trp Ser Gln Leu Leu Leu Leu Lys Ala Gly His Arg Leu Ser Val Gly 260 265 270 Leu Arg Ala Tyr Leu His Gly Ala Gln Asp Ala Tyr Arg Asp Trp Glu 275 280 285 Leu Ser Tyr Pro Asn Thr Thr Ser Phe Gly Leu Phe Leu Val Lys Pro 290 295 300 Asp Asn Pro Trp Glu 305 <210> SEQ ID NO 43 <211> LENGTH: 273 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 43 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Arg Thr Glu Pro Arg Pro Ala Leu Thr Ile Thr Thr Ser 65 70 75 80 Pro Asn Leu Gly Thr Arg Glu Asn Asn Ala Asp Gln Val Thr Pro Val 85 90 95 Ser His Ile Gly Cys Pro Asn Thr Thr Gln Gln Gly Ser Pro Val Phe 100 105 110 Ala Lys Leu Leu Ala Lys Asn Gln Ala Ser Leu Cys Asn Thr Thr Leu 115 120 125 Asn Trp His Ser Gln Asp Gly Ala Gly Ser Ser Tyr Leu Ser Gln Gly 130 135 140 Leu Arg Tyr Glu Glu Asp Lys Lys Glu Leu Val Val Asp Ser Pro Gly 145 150 155 160 Leu Tyr Tyr Val Phe Leu Glu Leu Lys Leu Ser Pro Thr Phe Thr Asn 165 170 175 Thr Gly His Lys Val Gln Gly Trp Val Ser Leu Val Leu Gln Ala Lys 180 185 190 Pro Gln Val Asp Asp Phe Asp Asn Leu Ala Leu Thr Val Glu Leu Phe 195 200 205 Pro Cys Ser Met Glu Asn Lys Leu Val Asp Arg Ser Trp Ser Gln Leu 210 215 220 Leu Leu Leu Lys Ala Gly His Arg Leu Ser Val Gly Leu Arg Ala Tyr 225 230 235 240 Leu His Gly Ala Gln Asp Ala Tyr Arg Asp Trp Glu Leu Ser Tyr Pro 245 250 255 Asn Thr Thr Ser Phe Gly Leu Phe Leu Val Lys Pro Asp Asn Pro Trp 260 265 270 Glu <210> SEQ ID NO 44 <211> LENGTH: 206 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 44 Arg Thr Glu Pro Arg Pro Ala Leu Thr Ile Thr Thr Ser Pro Asn Leu 1 5 10 15 Gly Thr Arg Glu Asn Asn Ala Asp Gln Val Thr Pro Val Ser His Ile 20 25 30 Gly Cys Pro Asn Thr Thr Gln Gln Gly Ser Pro Val Phe Ala Lys Leu 35 40 45 Leu Ala Lys Asn Gln Ala Ser Leu Cys Asn Thr Thr Leu Asn Trp His 50 55 60 Ser Gln Asp Gly Ala Gly Ser Ser Tyr Leu Ser Gln Gly Leu Arg Tyr 65 70 75 80 Glu Glu Asp Lys Lys Glu Leu Val Val Asp Ser Pro Gly Leu Tyr Tyr 85 90 95 Val Phe Leu Glu Leu Lys Leu Ser Pro Thr Phe Thr Asn Thr Gly His 100 105 110 Lys Val Gln Gly Trp Val Ser Leu Val Leu Gln Ala Lys Pro Gln Val 115 120 125 Asp Asp Phe Asp Asn Leu Ala Leu Thr Val Glu Leu Phe Pro Cys Ser 130 135 140 Met Glu Asn Lys Leu Val Asp Arg Ser Trp Ser Gln Leu Leu Leu Leu 145 150 155 160 Lys Ala Gly His Arg Leu Ser Val Gly Leu Arg Ala Tyr Leu His Gly 165 170 175 Ala Gln Asp Ala Tyr Arg Asp Trp Glu Leu Ser Tyr Pro Asn Thr Thr 180 185 190 Ser Phe Gly Leu Phe Leu Val Lys Pro Asp Asn Pro Trp Glu 195 200 205 <210> SEQ ID NO 45 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 45 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> SEQ ID NO 46 <211> LENGTH: 540 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 46 Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe 115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu 180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile 195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr 210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr 260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg 275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala 290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly 325 330 335 Gly Ser Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp 340 345 350 Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala 355 360 365 Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro 370 375 380 Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr 385 390 395 400 Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser 405 410 415 Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu 420 425 430 Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile 435 440 445 Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala 450 455 460 Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met 465 470 475 480 Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu 485 490 495 Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr 500 505 510 Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val 515 520 525 Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 530 535 540 <210> SEQ ID NO 47 <211> LENGTH: 328 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47 Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe 115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu 180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile 195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr 210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr 260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg 275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala 290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser 325 <210> SEQ ID NO 48 <211> LENGTH: 197 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48 Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu 1 5 10 15 His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys 20 25 30 Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp 35 40 45 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 50 55 60 Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr 65 70 75 80 Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 85 90 95 Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100 105 110 Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115 120 125 Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu 130 135 140 Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser 145 150 155 160 Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 165 170 175 Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser 180 185 190 Tyr Leu Asn Ala Ser 195 <210> SEQ ID NO 49 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 49 gtcgacgcca cc 12 <210> SEQ ID NO 50 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 50 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys 20 <210> SEQ ID NO 51 <211> LENGTH: 33 <212> TYPE: PRT <213> ORGANISM: Saccharomyces cerevisiae <400> SEQUENCE: 51 Arg Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile 1 5 10 15 Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu 20 25 30 Arg <210> SEQ ID NO 52 <211> LENGTH: 126 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro Leu Pro Ser 1 5 10 15 Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn Lys Val Ser 20 25 30 Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu Ile Tyr Gly 35 40 45 Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro Phe Glu Val 50 55 60 Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr Asn Lys Ser 65 70 75 80 Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val Gly Asp Thr 85 90 95 Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys Asn Asn Thr 100 105 110 Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile Ser 115 120 125 <210> SEQ ID NO 53 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 53 Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser 1 5 10 <210> SEQ ID NO 54 <211> LENGTH: 245 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 54 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala 65 70 75 80 Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp 85 90 95 Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr 100 105 110 Ala Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 130 135 140 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 145 150 155 160 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 165 170 175 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 180 185 190 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 195 200 205 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 210 215 220 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 225 230 235 240 Phe Ile Asn Thr Ser 245 <210> SEQ ID NO 55 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 55 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly 20 25 30 <210> SEQ ID NO 56 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr 1 5 10 15 Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly 20 25 30 Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala 35 40 45 His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val 50 55 60 His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr Ala 65 70 75 <210> SEQ ID NO 57 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 57 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 58 <211> LENGTH: 485 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 58 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Glu Ile Val Leu Thr Gln Ser Pro Ala Thr 20 25 30 Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser 35 40 45 Ser Ser Ile Ser Tyr Met His Trp Phe Gln Gln Arg Pro Gly Gln Ser 50 55 60 Pro Arg Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro 65 70 75 80 Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile 85 90 95 Ser Ser Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Arg 100 105 110 Thr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 130 135 140 Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala Ser 145 150 155 160 Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp 165 170 175 Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 180 185 190 Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn Glu Val Phe Lys 195 200 205 Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr Met 210 215 220 Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala 225 230 235 240 Arg Gly Asp Tyr Gly Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 245 250 255 Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 260 265 270 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 275 280 285 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 290 295 300 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 305 310 315 320 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 325 330 335 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 340 345 350 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 355 360 365 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 370 375 380 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 385 390 395 400 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 405 410 415 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 420 425 430 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 435 440 445 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 450 455 460 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 465 470 475 480 Leu Ser Pro Gly Lys 485 <210> SEQ ID NO 59 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Ile Ser Tyr Met 20 25 30 His Trp Phe Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys His Gln Arg Thr Ser Tyr Pro Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 60 <211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 60 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn Glu Val Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Asp Tyr Gly Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 61 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 61 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 62 <211> LENGTH: 245 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 62 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala 65 70 75 80 Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp 85 90 95 Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr 100 105 110 Ala Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 130 135 140 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 145 150 155 160 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 165 170 175 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 180 185 190 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 195 200 205 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 210 215 220 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 225 230 235 240 Phe Ile Asn Thr Ser 245 <210> SEQ ID NO 63 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly 20 25 30 <210> SEQ ID NO 64 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 64 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 65 <211> LENGTH: 261 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 65 Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly 1 5 10 15 Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val 50 55 60 Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys 85 90 95 Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu 100 105 110 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 115 120 125 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 130 135 140 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 145 150 155 160 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 165 170 175 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 180 185 190 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 195 200 205 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 210 215 220 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 225 230 235 240 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 245 250 255 Gly Leu Leu Lys Leu 260 <210> SEQ ID NO 66 <211> LENGTH: 183 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 66 Met Glu Arg Val Gln Pro Leu Glu Glu Asn Val Gly Asn Ala Ala Arg 1 5 10 15 Pro Arg Phe Glu Arg Asn Lys Leu Leu Leu Val Ala Ser Val Ile Gln 20 25 30 Gly Leu Gly Leu Leu Leu Cys Phe Thr Tyr Ile Cys Leu His Phe Ser 35 40 45 Ala Leu Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val 50 55 60 Gln Phe Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln 65 70 75 80 Lys Glu Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn 85 90 95 Cys Asp Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu 100 105 110 Val Asn Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln 115 120 125 Leu Lys Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr 130 135 140 Tyr Lys Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu 145 150 155 160 Asp Asp Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn 165 170 175 Pro Gly Glu Phe Cys Val Leu 180 <210> SEQ ID NO 67 <211> LENGTH: 462 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 67 Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg 1 5 10 15 Leu Gly Ser Asp Ala His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val 20 25 30 Trp Phe Glu Ala Glu Phe Phe His His Ile Leu His Trp Thr Pro Ile 35 40 45 Pro Asn Gln Ser Glu Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr 50 55 60 Gly Ile Glu Ser Trp Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser 65 70 75 80 Tyr Asp Leu Thr Ala Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr 85 90 95 Arg Ala Arg Val Arg Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr 100 105 110 Val Thr Asn Thr Arg Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly 115 120 125 Ser Val Asn Leu Glu Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln 130 135 140 Leu Pro Arg Pro Lys Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile 145 150 155 160 Phe Ser His Phe Arg Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly 165 170 175 Asn Phe Thr Phe Thr His Lys Lys Val Lys His Glu Asn Phe Ser Leu 180 185 190 Leu Thr Ser Gly Glu Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser 195 200 205 Val Ala Ser Arg Ser Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile 210 215 220 Ser Leu Thr Arg Gln Tyr Phe Thr Val Thr Asn Asp Lys Thr His Thr 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 275 280 285 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 305 310 315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 325 330 335 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 355 360 365 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 420 425 430 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435 440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 68 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val Trp Phe Glu Ala Glu 1 5 10 15 Phe Phe His His Ile Leu His Trp Thr Pro Ile Pro Asn Gln Ser Glu 20 25 30 Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr Gly Ile Glu Ser Trp 35 40 45 Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser Tyr Asp Leu Thr Ala 50 55 60 Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr Arg Ala Arg Val Arg 65 70 75 80 Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr Val Thr Asn Thr Arg 85 90 95 Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly Ser Val Asn Leu Glu 100 105 110 Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln Leu Pro Arg Pro Lys 115 120 125 Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile Phe Ser His Phe Arg 130 135 140 Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly Asn Phe Thr Phe Thr 145 150 155 160 His Lys Lys Val Lys His Glu Asn Phe Ser Leu Leu Thr Ser Gly Glu 165 170 175 Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser Val Ala Ser Arg Ser 180 185 190 Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile Ser Leu Thr Arg Gln 195 200 205 Tyr Phe Thr Val Thr Asn 210 <210> SEQ ID NO 69 <211> LENGTH: 21 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 69 Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg 1 5 10 15 Leu Gly Ser Asp Ala 20 <210> SEQ ID NO 70 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 70 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 71 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 71 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro 65 70 75 80 Leu Pro Ser Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn 85 90 95 Lys Val Ser Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu 100 105 110 Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro 115 120 125 Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr 130 135 140 Asn Lys Ser Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val 145 150 155 160 Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys 165 170 175 Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile 180 185 190 Ser <210> SEQ ID NO 72 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val Gln Phe 1 5 10 15 Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln Lys Glu 20 25 30 Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn Cys Asp 35 40 45 Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu Val Asn 50 55 60 Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln Leu Lys 65 70 75 80 Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr Tyr Lys 85 90 95 Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu Asp Asp 100 105 110 Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn Pro Gly 115 120 125 Glu Phe Cys Val Leu 130 <210> SEQ ID NO 73 <211> LENGTH: 216 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 73 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His 65 70 75 80 Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala 85 90 95 Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn 100 105 110 Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala 115 120 125 Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe 130 135 140 Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu 145 150 155 160 Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln 165 170 175 Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val 180 185 190 Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe 195 200 205 Thr Ser Phe Gly Leu Leu Lys Leu 210 215 <210> SEQ ID NO 74 <400> SEQUENCE: 74 000 <210> SEQ ID NO 75 <400> SEQUENCE: 75 000 <210> SEQ ID NO 76 <211> LENGTH: 149 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 76 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 1 5 10 15 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 20 25 30 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 35 40 45 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 50 55 60 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 65 70 75 80 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 85 90 95 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 100 105 110 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 115 120 125 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 130 135 140 Gly Leu Leu Lys Leu 145 <210> SEQ ID NO 77 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 77 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His <210> SEQ ID NO 78 <211> LENGTH: 144 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 78 Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile 1 5 10 15 Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His 20 25 30 Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp 35 40 45 Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe 50 55 60 Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys 65 70 75 80 Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met 85 90 95 Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser 100 105 110 Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys 115 120 125 Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 130 135 140 <210> SEQ ID NO 79 <211> LENGTH: 144 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 79 Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile 1 5 10 15 Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His 20 25 30 Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp 35 40 45 Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe 50 55 60 Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys 65 70 75 80 Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met 85 90 95 Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser 100 105 110 Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys 115 120 125 Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 130 135 140 <210> SEQ ID NO 80 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 80 Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro <210> SEQ ID NO 81 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 81 Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro <210> SEQ ID NO 82 <211> LENGTH: 387 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 82 atgactgaca ccctagatct agaaatggac ggaattatta cagagcagcg cctgctagaa 60 agacgcaggg cagcggccga gcaacagcgc atgaatcaag agctccaaga catggttaac 120 ttgcaccagt gcaaaagggg tatcttttgt ctggtaaagc aggccaaagt cacctacgac 180 agtaatacca ccggacaccg ccttagctac aagttgccaa ccaagcgtca gaaattggtg 240 gtcatggtgg gagaaaagcc cattaccata actcagcact cggtagaaac cgaaggctgc 300 attcactcac cttgtcaagg acctgaggat ctctgcaccc ttattaagac cctgtgcggt 360 ctcaaagatc ttattccctt taactaa 387 <210> SEQ ID NO 83 <211> LENGTH: 399 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 83 atgaaattta ctgtgacttt tctgctgatt atttgcaccc tatctgcgtt ttgttccccg 60 acctccaagc ctcaaagaca tatatcatgc agattcactc gtatatggaa tattccaagt 120 tgctacaatg aaaaaagcga tctttccgaa gcctggttat atgcaatcat ctctgttatg 180 gtgttctgca gtaccatctt agccctagct atatatccct accttgacat tggctggaac 240 gcaatagatg ccatgaacca cccaactttc cccgcgcccg ctatgcttcc actgcaacaa 300 gttgttgccg gcggctttgt cccagccaat cagcctcgcc caccttctcc cacccccact 360 gaaatcagct actttaatct aacaggagga gatgactga 399 <210> SEQ ID NO 84 <211> LENGTH: 192 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 84 atgattcctc gagtttttat attactgacc cttgttgcgc tttttttgtg cgtgctccac 60 attggctgcg gtttctcaca tcgaagtaga ctgcattcca gccttcacag tctatttgct 120 ttacggattt gtcaccctca cgctcatctg cagcctcatc actgtggtca tcgcctttat 180 ccagtgcatt ga 192 <210> SEQ ID NO 85 <211> LENGTH: 282 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 85 atgaccaaca caaccaacgc ggccgccgct accggactta catctaccac aaatacaccc 60 caagtttctg cctttgtcaa taactgggat aacttgggca tgtggtggtt ctccatagcg 120 cttatgtttg tatgccttat tattatgtgg ctcatctgct gcctaaagcg caaacgcgcc 180 cgaccaccca tctatagtcc catcattgtg ctacacccaa acaatgatgg aatccataga 240 ttggacggac tgaaacacat gttcttttct cttacagtat ga 282 <210> SEQ ID NO 86 <211> LENGTH: 483 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 86 atgattaggt acataatcct aggtttactc acccttgcgt cagcccacgg taccacccaa 60 aaggtggatt ttaaggagcc agcctgtaat gttacattcg cagctgaagc taatgagtgc 120 accactctta taaaatgcac cacagaacat gaaaagctgc ttattcgcca caaaaacaaa 180 attggcaagt atgctgttta tgctatttgg cagccaggtg acactacaga gtataatgtt 240 acagttttcc agggtaaaag tcataaaact tttatgtata cttttccatt ttatgaaatg 300 tgcgacatta ccatgtacat gagcaaacag tataagttgt ggcccccaca aaattgtgtg 360 gaaaacactg gcactttctg ctgcactgct atgctaatta cagtgctcgc tttggtctgt 420 accctactct atattaaata caaaagcaga cgcagcttta ttgaggaaaa gaaaatgcct 480 taa 483 <210> SEQ ID NO 87 <211> LENGTH: 192 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 87 atgaacaatt caagcaactc tacgggctat tctaattcag gtttctctag aatcggggtt 60 ggggttattc tctgtcttgt gattctcttt attcttatac taacgcttct ctgcctaagg 120 ctcgccgcct gctgtgtgca catttgcatt tattgtcagc tttttaaacg ctggggtcgc 180 cacccaagat ga 192 <210> SEQ ID NO 88 <211> LENGTH: 324 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 88 atgttaagtg gagaggcaga gcaactgcgc ctgaaacacc tggtccactg tcgccgccac 60 aagtgctttg cccgcgactc cggtgagttt tgctactttg aattgcccga ggatcatatc 120 gagggcccgg cgcacggcgt ccggcttacc gcccagggag agcttgcccg tagcctgatt 180 cgggagttta cccagcgccc cctgctagtt gagcgggaca ggggaccctg tgttctcact 240 gtgatttgca actgtcctaa ccctggatta catcaagatc tttgttgcca tctctgtgct 300 gagtataata aatacagaaa ttaa 324 <210> SEQ ID NO 89 <211> LENGTH: 379 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 89 caccctagat ctagaaatgg acggaattat tacagagcag cgcctgctag aaagacgcag 60 ggcagcggcc gagcaacagc gcatgaatca agagctccaa gacatggtta acttgcacca 120 gtgcaaaagg ggtatctttt gtctggtaaa gcaggccaaa gtcacctacg acagtaatac 180 caccggacac cgccttagct acaagttgcc aaccaagcgt cagaaattgg tggtcatggt 240 gggagaaaag cccattacca taactcagca ctcggtagaa accgaaggct gcattcactc 300 accttgtcaa ggacctgagg atctctgcac ccttattaag accctgtgcg gtctcaaaga 360 tcttattccc tttaactaa 379 <210> SEQ ID NO 90 <211> LENGTH: 755 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 90 agacgcccag gccgaagttc agatgactaa ctcaggggcg cagcttgcgg gcggctttcg 60 tcacagggtg cggtcgcccg ggcagggtat aactcacctg acaatcagag ggcgaggtat 120 tcagctcaac gacgagtcgg tgagctcctc gcttggtctc cgtccggacg ggacatttca 180 gatcggcggc gccggccgct cttcattcac gcctcgtcag gcaatcctaa ctctgcagac 240 ctcgtcctct gagccgcgct ctggaggcat tggaactctg caatttattg aggagtttgt 300 gccatcggtc tactttaacc ccttctcggg acctcccggc cactatccgg atcaatttat 360 tcctaacttt gacgcggtaa aggactcggc ggacggctac gactgaatgt taagtggaga 420 ggcagagcaa ctgcgcctga aacacctggt ccactgtcgc cgccacaagt gctttgcccg 480 cgactccggt gagttttgct actttgaatt gcccgaggat catatcgagg gcccggcgca 540 cggcgtccgg cttaccgccc agggagagct tgcccgtagc ctgattcggg agtttaccca 600 gcgccccctg ctagttgagc gggacagggg accctgtgtt ctcactgtga tttgcaactg 660 tcctaaccct ggattacatc aagatcctct agttaatgtc aggtcgccta agtcgattaa 720 ctagagtacc cggggatctt attcccttta actaa 755 <210> SEQ ID NO 91 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 91 gatcttattc cctttaacta a 21 <210> SEQ ID NO 92 <211> LENGTH: 279 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 92 atgttaagtg gagaggcaga gcaactgcgc ctgaaacacc tggtccactg tcgccgccac 60 aagtgctttg cccgcgactc cggtgagttt tgctactttg aattgcccga ggatcatatc 120 gagggcccgg cgcacggcgt ccggcttacc gcccagggag agcttgcccg tagcctgatt 180 cgggagttta cccagcgccc cctgctagtt gagcgggaca ggggaccctg tgttctcact 240 gtgatttgca actgtcctaa ccctggatta catcaagat 279 <210> SEQ ID NO 93 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 93 agacgcccag gccgaagttc agatgacta 29 <210> SEQ ID NO 94 <211> LENGTH: 33225 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 94 ttttggattg aagccaatat gataatgagg gggtggagtt tgtgacgtgg cgcggggcgt 60 gggaacgggg cgggtgacgt agtagtgtgg cggaagtgtg atgttgcaag tgtggcggaa 120 cacatgtaag cgacggatgt ggcaaaagtg acgtttttgg tgtgcgccgg tgttttgggc 180 gtaaccgagt aagatttggc cattttcgcg ggaaaactga ataagaggaa gtgaaatctg 240 aataattttg tgttactcat agcgcgtaat atttgtctag ggccgcgggg actttgaccg 300 tttacgtgga gactcgccca ggtgtttttc tcaggtgttt tccgcgttcc gggtcaaagt 360 tggcgtttta ttattatagt cagctgacgt gtagtgtatt tatacccggt gagttcctca 420 agaggccact cttgagtgcc agcgagtaga gttttctcct ccgagccgct ccgacaccgg 480 gactgaaaat gagacatatt atctgccacg gaggtgttat taccgaagaa atggccgcca 540 gtcttttgga ccagctgatc gaagaggtac tggctgataa tcttccacct cctagccatt 600 ttgaaccacc tacccttcac gaactgtatg atttagacgt gacggccccc gaagatccca 660 acgaggaggc ggtttcgcag atttttcccg actctgtaat gttggcggtg caggaaggga 720 ttgacttact cacttttccg ccggcgcccg gttctccgga gccgcctcac ctttcccggc 780 agcccgagca gccggagcag agagccttgg gtccggtttc tatgccaaac cttgtaccgg 840 aggtgatcga tcttacctgc cacgaggctg gctttccacc cagtgacgac gaggatgaag 900 agggtgagga gtttgtgtta gattatgtgg agcaccccgg gcacggttgc aggtcttgtc 960 attatcaccg gaggaatacg ggggacccag atattatgtg ttcgctttgc tatatgagga 1020 cctgtggcat gtttgtctac agtaagtgaa aattatgggc agtgggtgat agagtggtgg 1080 gtttggtgtg gtaatttttt ttttaatttt tacagttttg tggtttaaag aattttgtat 1140 tgtgattttt ttaaaaggtc ctgtgtctga acctgagcct gagcccgagc cagaaccgga 1200 gcctgcaaga cctacccgcc gtcctaaaat ggcgcctgct atcctgagac gcccgacatc 1260 acctgtgtct agagaatgca atagtagtac ggatagctgt gactccggtc cttctaacac 1320 acctcctgag atacacccgg tggtcccgct gtgccccatt aaaccagttg ccgtgagagt 1380 tggtgggcgt cgccaggctg tggaatgtat cgaggacttg cttaacgagc ctgggcaacc 1440 tttggacttg agctgtaaac gccccaggcc ataaggtgta aacctgtgat tgcgtgtgtg 1500 gttaacgcct ttgtttgctg aatgagttga tgtaagttta ataaagggtg agataatgtt 1560 taacttgcat ggcgtgttaa atggggcggg gcttaaaggg tatataatgc gccgtgggct 1620 aatcttggtt acatctgacc tcgtcgacgc ttgggagtgt ttggaagatt tttctgctgt 1680 gcgtaacttg ctggaacaga gctctaacag tacctcttgg ttttggaggt ttctgtgggg 1740 ctcatcccag gcaaagttag tctgcagaat taaggaggat tacaagtggg aatttgaaga 1800 gcttttgaaa tcctgtggtg agctgtttga ttctttgaac tcgagtcacc aggcgctttt 1860 ccaagagaag gtcatcaaga ctttggattt ttccacaccg gggcgcgctg cggctgctgt 1920 tgcttttttg agttttataa aggataaatg gagcgaagaa acccatctga gcggggggta 1980 cctgctggat tttctggcca tgcatctgtg gagagcggtt gtgagacaca agaatcgcct 2040 gctactgttg tcttccgtcc gcccggcgat aataccgacg gaggagcagc agcagcagca 2100 ggaggaagcc aggcggcggc ggcaggagca gagcccatgg aacccgagag ccggcctgga 2160 ccctcgggaa tgaatgttgt acaggtggct gaactgtatc cagaactgag acgcattttg 2220 acaattacag aggatgggca ggggctaaag ggggtaaaga gggagcgggg ggcttgtgag 2280 gctacagagg aggctaggaa tctagctttt agcttaatga ccagacaccg tcctgagtgt 2340 attacttttc aacagatcaa ggataattgc gctaatgagc ttgatctgct ggcgcagaag 2400 tattccatag agcagctgac cacttactgg ctgcagccag gggatgattt tgaggaggct 2460 attagggtat atgcaaaggt ggcacttagg ccagattgca agtacaagat cagcaaactt 2520 gtaaatatca ggaattgttg ctacatttct gggaacgggg ccgaggtgga gatagatacg 2580 gaggataggg tggcctttag atgtagcatg ataaatatgt ggccgggggt gcttggcatg 2640 gacggggtgg ttattatgaa tgtaaggttt actggcccca attttagcgg tacggttttc 2700 ctggccaata ccaaccttat cctacacggt gtaagcttct atgggtttaa caatacctgt 2760 gtggaagcct ggaccgatgt aagggttcgg ggctgtgcct tttactgctg ctggaagggg 2820 gtggtgtgtc gccccaaaag cagggcttca attaagaaat gcctctttga aaggtgtacc 2880 ttgggtatcc tgtctgaggg taactccagg gtgcgccaca atgtggcctc cgactgtggt 2940 tgcttcatgc tagtgaaaag cgtggctgtg attaagcata acatggtatg tggcaactgc 3000 gaggacaggg cctctcagat gctgacctgc tcggacggca actgtcacct gctgaagacc 3060 attcacgtag ccagccactc tcgcaaggcc tggccagtgt ttgagcataa catactgacc 3120 cgctgttcct tgcatttggg taacaggagg ggggtgttcc taccttacca atgcaatttg 3180 agtcacacta agatattgct tgagcccgag agcatgtcca aggtgaacct gaacggggtg 3240 tttgacatga ccatgaagat ctggaaggtg ctgaggtacg atgagacccg caccaggtgc 3300 agaccctgcg agtgtggcgg taaacatatt aggaaccagc ctgtgatgct ggatgtgacc 3360 gaggagctga ggcccgatca cttggtgctg gcctgcaccc gcgctgagtt tggctctagc 3420 gatgaagata cagattgagg tactgaaatg tgtgggcgtg gcttaagggt gggaaagaat 3480 atataaggtg ggggtcttat gtagttttgt atctgttttg cagcagccgc cgccgccatg 3540 agcaccaact cgtttgatgg aagcattgtg agctcatatt tgacaacgcg catgccccca 3600 tgggccgggg tgcgtcagaa tgtgatgggc tccagcattg atggtcgccc cgtcctgccc 3660 gcaaactcta ctaccttgac ctacgagacc gtgtctggaa cgccgttgga gactgcagcc 3720 tccgccgccg cttcagccgc tgcagccacc gcccgcggga ttgtgactga ctttgctttc 3780 ctgagcccgc ttgcaagcag tgcagcttcc cgttcatccg cccgcgatga caagttgacg 3840 gctcttttgg cacaattgga ttctttgacc cgggaactta atgtcgtttc tcagcagctg 3900 ttggatctgc gccagcaggt ttctgccctg aaggcttcct cccctcccaa tgcggtttaa 3960 aacataaata aaaaaccaga ctctgtttgg atttggatca agcaagtgtc ttgctgtctt 4020 tatttagggg ttttgcgcgc gcggtaggcc cgggaccagc ggtctcggtc gttgagggtc 4080 ctgtgtattt tttccaggac gtggtaaagg tgactctgga tgttcagata catgggcata 4140 agcccgtctc tggggtggag gtagcaccac tgcagagctt catgctgcgg ggtggtgttg 4200 tagatgatcc agtcgtagca ggagcgctgg gcgtggtgcc taaaaatgtc tttcagtagc 4260 aagctgattg ccaggggcag gcccttggtg taagtgttta caaagcggtt aagctgggat 4320 gggtgcatac gtggggatat gagatgcatc ttggactgta tttttaggtt ggctatgttc 4380 ccagccatat ccctccgggg attcatgttg tgcagaacca ccagcacagt gtatccggtg 4440 cacttgggaa atttgtcatg tagcttagaa ggaaatgcgt ggaagaactt ggagacgccc 4500 ttgtgacctc caagattttc catgcattcg tccataatga tggcaatggg cccacgggcg 4560 gcggcctggg cgaagatatt tctgggatca ctaacgtcat agttgtgttc caggatgaga 4620 tcgtcatagg ccatttttac aaagcgcggg cggagggtgc cagactgcgg tataatggtt 4680 ccatccggcc caggggcgta gttaccctca cagatttgca tttcccacgc tttgagttca 4740 gatgggggga tcatgtctac ctgcggggcg atgaagaaaa cggtttccgg ggtaggggag 4800 atcagctggg aagaaagcag gttcctgagc agctgcgact taccgcagcc ggtgggcccg 4860 taaatcacac ctattaccgg ctgcaactgg tagttaagag agctgcagct gccgtcatcc 4920 ctgagcaggg gggccacttc gttaagcatg tccctgactc gcatgttttc cctgaccaaa 4980 tccgccagaa ggcgctcgcc gcccagcgat agcagttctt gcaaggaagc aaagtttttc 5040 aacggtttga gaccgtccgc cgtaggcatg cttttgagcg tttgaccaag cagttccagg 5100 cggtcccaca gctcggtcac ctgctctacg gcatctcgat ccagcatatc tcctcgtttc 5160 gcgggttggg gcggctttcg ctgtacggca gtagtcggtg ctcgtccaga cgggccaggg 5220 tcatgtcttt ccacgggcgc agggtcctcg tcagcgtagt ctgggtcacg gtgaaggggt 5280 gcgctccggg ctgcgcgctg gccagggtgc gcttgaggct ggtcctgctg gtgctgaagc 5340 gctgccggtc ttcgccctgc gcgtcggcca ggtagcattt gaccatggtg tcatagtcca 5400 gcccctccgc ggcgtggccc ttggcgcgca gcttgccctt ggaggaggcg ccgcacgagg 5460 ggcagtgcag acttttgagg gcgtagagct tgggcgcgag aaataccgat tccggggagt 5520 aggcatccgc gccgcaggcc ccgcagacgg tctcgcattc cacgagccag gtgagctctg 5580 gccgttcggg gtcaaaaacc aggtttcccc catgcttttt gatgcgtttc ttacctctgg 5640 tttccatgag ccggtgtcca cgctcggtga cgaaaaggct gtccgtgtcc ccgtatacag 5700 acttgagagg cctgtcctcg agcggtgttc cgcggtcctc ctcgtataga aactcggacc 5760 actctgagac aaaggctcgc gtccaggcca gcacgaagga ggctaagtgg gaggggtagc 5820 ggtcgttgtc cactaggggg tccactcgct ccagggtgtg aagacacatg tcgccctctt 5880 cggcatcaag gaaggtgatt ggtttgtagg tgtaggccac gtgaccgggt gttcctgaag 5940 gggggctata aaagggggtg ggggcgcgtt cgtcctcact ctcttccgca tcgctgtctg 6000 cgagggccag ctgttggggt gagtactccc tctgaaaagc gggcatgact tctgcgctaa 6060 gattgtcagt ttccaaaaac gaggaggatt tgatattcac ctggcccgcg gtgatgcctt 6120 tgagggtggc cgcatccatc tggtcagaaa agacaatctt tttgttgtca agcttggtgg 6180 caaacgaccc gtagagggcg ttggacagca acttggcgat ggagcgcagg gtttggtttt 6240 tgtcgcgatc ggcgcgctcc ttggccgcga tgtttagctg cacgtattcg cgcgcaacgc 6300 accgccattc gggaaagacg gtggtgcgct cgtcgggcac caggtgcacg cgccaaccgc 6360 ggttgtgcag ggtgacaagg tcaacgctgg tggctacctc tccgcgtagg cgctcgttgg 6420 tccagcagag gcggccgccc ttgcgcgagc agaatggcgg tagggggtct agctgcgtct 6480 cgtccggggg gtctgcgtcc acggtaaaga ccccgggcag caggcgcgcg tcgaagtagt 6540 ctatcttgca tccttgcaag tctagcgcct gctgccatgc gcgggcggca agcgcgcgct 6600 cgtatgggtt gagtggggga ccccatggca tggggtgggt gagcgcggag gcgtacatgc 6660 cgcaaatgtc gtaaacgtag aggggctctc tgagtattcc aagatatgta gggtagcatc 6720 ttccaccgcg gatgctggcg cgcacgtaat cgtatagttc gtgcgaggga gcgaggaggt 6780 cgggaccgag gttgctacgg gcgggctgct ctgctcggaa gactatctgc ctgaagatgg 6840 catgtgagtt ggatgatatg gttggacgct ggaagacgtt gaagctggcg tctgtgagac 6900 ctaccgcgtc acgcacgaag gaggcgtagg agtcgcgcag cttgttgacc agctcggcgg 6960 tgacctgcac gtctagggcg cagtagtcca gggtttcctt gatgatgtca tacttatcct 7020 gtcccttttt tttccacagc tcgcggttga ggacaaactc ttcgcggtct ttccagtact 7080 cttggatcgg aaacccgtcg gcctccgaac ggtaagagcc tagcatgtag aactggttga 7140 cggcctggta ggcgcagcat cccttttcta cgggtagcgc gtatgcctgc gcggccttcc 7200 ggagcgaggt gtgggtgagc gcaaaggtgt ccctgaccat gactttgagg tactggtatt 7260 tgaagtcagt gtcgtcgcat ccgccctgct cccagagcaa aaagtccgtg cgctttttgg 7320 aacgcggatt tggcagggcg aaggtgacat cgttgaagag tatctttccc gcgcgaggca 7380 taaagttgcg tgtgatgcgg aagggtcccg gcacctcgga acggttgtta attacctggg 7440 cggcgagcac gatctcgtca aagccgttga tgttgtggcc cacaatgtaa agttccaaga 7500 agcgcgggat gcccttgatg gaaggcaatt ttttaagttc ctcgtaggtg agctcttcag 7560 gggagctgag cccgtgctct gaaagggccc agtctgcaag atgagggttg gaagcgacga 7620 atgagctcca caggtcacgg gccattagca tttgcaggtg gtcgcgaaag gtcctaaact 7680 ggcgacctat ggccattttt tctggggtga tgcagtagaa ggtaagcggg tcttgttccc 7740 agcggtccca tccaaggttc gcggctaggt ctcgcgcggc agtcactaga ggctcatctc 7800 cgccgaactt catgaccagc atgaagggca cgagctgctt cccaaaggcc cccatccaag 7860 tataggtctc tacatcgtag gtgacaaaga gacgctcggt gcgaggatgc gagccgatcg 7920 ggaagaactg gatctcccgc caccaattgg aggagtggct attgatgtgg tgaaagtaga 7980 agtccctgcg acgggccgaa cactcgtgct ggcttttgta aaaacgtgcg cagtactggc 8040 agcggtgcac gggctgtaca tcctgcacga ggttgacctg acgaccgcgc acaaggaagc 8100 agagtgggaa tttgagcccc tcgcctggcg ggtttggctg gtggtcttct acttcggctg 8160 cttgtccttg accgtctggc tgctcgaggg gagttacggt ggatcggacc accacgccgc 8220 gcgagcccaa agtccagatg tccgcgcgcg gcggtcggag cttgatgaca acatcgcgca 8280 gatgggagct gtccatggtc tggagctccc gcggcgtcag gtcaggcggg agctcctgca 8340 ggtttacctc gcatagacgg gtcagggcgc gggctagatc caggtgatac ctaatttcca 8400 ggggctggtt ggtggcggcg tcgatggctt gcaagaggcc gcatccccgc ggcgcgacta 8460 cggtaccgcg cggcgggcgg tgggccgcgg gggtgtcctt ggatgatgca tctaaaagcg 8520 gtgacgcggg cgagcccccg gaggtagggg gggctccgga cccgccggga gagggggcag 8580 gggcacgtcg gcgccgcgcg cgggcaggag ctggtgctgc gcgcgtaggt tgctggcgaa 8640 cgcgacgacg cggcggttga tctcctgaat ctggcgcctc tgcgtgaaga cgacgggccc 8700 ggtgagcttg aacctgaaag agagttcgac agaatcaatt tcggtgtcgt tgacggcggc 8760 ctggcgcaaa atctcctgca cgtctcctga gttgtcttga taggcgatct cggccatgaa 8820 ctgctcgatc tcttcctcct ggagatctcc gcgtccggct cgctccacgg tggcggcgag 8880 gtcgttggaa atgcgggcca tgagctgcga gaaggcgttg aggcctccct cgttccagac 8940 gcggctgtag accacgcccc cttcggcatc gcgggcgcgc atgaccacct gcgcgagatt 9000 gagctccacg tgccgggcga agacggcgta gtttcgcagg cgctgaaaga ggtagttgag 9060 ggtggtggcg gtgtgttctg ccacgaagaa gtacataacc cagcgtcgca acgtggattc 9120 gttgatatcc cccaaggcct caaggcgctc catggcctcg tagaagtcca cggcgaagtt 9180 gaaaaactgg gagttgcgcg ccgacacggt taactcctcc tccagaagac ggatgagctc 9240 ggcgacagtg tcgcgcacct cgcgctcaaa ggctacaggg gcctcttctt cttcttcaat 9300 ctcctcttcc ataagggcct ccccttcttc ttcttctggc ggcggtgggg gaggggggac 9360 acggcggcga cgacggcgca ccgggaggcg gtcgacaaag cgctcgatca tctccccgcg 9420 gcgacggcgc atggtctcgg tgacggcgcg gccgttctcg cgggggcgca gttggaagac 9480 gccgcccgtc atgtcccggt tatgggttgg cggggggctg ccatgcggca gggatacggc 9540 gctaacgatg catctcaaca attgttgtgt aggtactccg ccgccgaggg acctgagcga 9600 gtccgcatcg accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca 9660 aggtaggctg agcaccgtgg cgggcggcag cgggcggcgg tcggggttgt ttctggcgga 9720 ggtgctgctg atgatgtaat taaagtaggc ggtcttgaga cggcggatgg tcgacagaag 9780 caccatgtcc ttgggtccgg cctgctgaat gcgcaggcgg tcggccatgc cccaggcttc 9840 gttttgacat cggcgcaggt ctttgtagta gtcttgcatg agcctttcta ccggcacttc 9900 ttcttctcct tcctcttgtc ctgcatctct tgcatctatc gctgcggcgg cggcggagtt 9960 tggccgtagg tggcgccctc ttcctcccat gcgtgtgacc ccgaagcccc tcatcggctg 10020 aagcagggct aggtcggcga caacgcgctc ggctaatatg gcctgctgca cctgcgtgag 10080 ggtagactgg aagtcatcca tgtccacaaa gcggtggtat gcgcccgtgt tgatggtgta 10140 agtgcagttg gccataacgg accagttaac ggtctggtga cccggctgcg agagctcggt 10200 gtacctgaga cgcgagtaag ccctcgagtc aaatacgtag tcgttgcaag tccgcaccag 10260 gtactggtat cccaccaaaa agtgcggcgg cggctggcgg tagaggggcc agcgtagggt 10320 ggccggggct ccgggggcga gatcttccaa cataaggcga tgatatccgt agatgtacct 10380 ggacatccag gtgatgccgg cggcggtggt ggaggcgcgc ggaaagtcgc ggacgcggtt 10440 ccagatgttg cgcagcggca aaaagtgctc catggtcggg acgctctggc cggtcaggcg 10500 cgcgcaatcg ttgacgctct agcgtgcaaa aggagagcct gtaagcgggc actcttccgt 10560 ggtctggtgg ataaattcgc aagggtatca tggcggacga ccggggttcg agccccgtat 10620 ccggccgtcc gccgtgatcc atgcggttac cgcccgcgtg tcgaacccag gtgtgcgacg 10680 tcagacaacg ggggagtgct ccttttggct tccttccagg cgcggcggct gctgcgctag 10740 cttttttggc cactggccgc gcgcagcgta agcggttagg ctggaaagcg aaagcattaa 10800 gtggctcgct ccctgtagcc ggagggttat tttccaaggg ttgagtcgcg ggacccccgg 10860 ttcgagtctc ggaccggccg gactgcggcg aacgggggtt tgcctccccg tcatgcaaga 10920 ccccgcttgc aaattcctcc ggaaacaggg acgagcccct tttttgcttt tcccagatgc 10980 atccggtgct gcggcagatg cgcccccctc ctcagcagcg gcaagagcaa gagcagcggc 11040 agacatgcag ggcaccctcc cctcctccta ccgcgtcagg aggggcgaca tccgcggttg 11100 acgcggcagc agatggtgat tacgaacccc cgcggcgccg ggcccggcac tacctggact 11160 tggaggaggg cgagggcctg gcgcggctag gagcgccctc tcctgagcgg cacccaaggg 11220 tgcagctgaa gcgtgatacg cgtgaggcgt acgtgccgcg gcagaacctg tttcgcgacc 11280 gcgagggaga ggagcccgag gagatgcggg atcgaaagtt ccacgcaggg cgcgagctgc 11340 ggcatggcct gaatcgcgag cggttgctgc gcgaggagga ctttgagccc gacgcgcgaa 11400 ccgggattag tcccgcgcgc gcacacgtgg cggccgccga cctggtaacc gcatacgagc 11460 agacggtgaa ccaggagatt aactttcaaa aaagctttaa caaccacgtg cgtacgcttg 11520 tggcgcgcga ggaggtggct ataggactga tgcatctgtg ggactttgta agcgcgctgg 11580 agcaaaaccc aaatagcaag ccgctcatgg cgcagctgtt ccttatagtg cagcacagca 11640 gggacaacga ggcattcagg gatgcgctgc taaacatagt agagcccgag ggccgctggc 11700 tgctcgattt gataaacatc ctgcagagca tagtggtgca ggagcgcagc ttgagcctgg 11760 ctgacaaggt ggccgccatc aactattcca tgcttagcct gggcaagttt tacgcccgca 11820 agatatacca taccccttac gttcccatag acaaggaggt aaagatcgag gggttctaca 11880 tgcgcatggc gctgaaggtg cttaccttga gcgacgacct gggcgtttat cgcaacgagc 11940 gcatccacaa ggccgtgagc gtgagccggc ggcgcgagct cagcgaccgc gagctgatgc 12000 acagcctgca aagggccctg gctggcacgg gcagcggcga tagagaggcc gagtcctact 12060 ttgacgcggg cgctgacctg cgctgggccc caagccgacg cgccctggag gcagctgggg 12120 ccggacctgg gctggcggtg gcacccgcgc gcgctggcaa cgtcggcggc gtggaggaat 12180 atgacgagga cgatgagtac gagccagagg acggcgagta ctaagcggtg atgtttctga 12240 tcagatgatg caagacgcaa cggacccggc ggtgcgggcg gcgctgcaga gccagccgtc 12300 cggccttaac tccacggacg actggcgcca ggtcatggac cgcatcatgt cgctgactgc 12360 gcgcaatcct gacgcgttcc ggcagcagcc gcaggccaac cggctctccg caattctgga 12420 agcggtggtc ccggcgcgcg caaaccccac gcacgagaag gtgctggcga tcgtaaacgc 12480 gctggccgaa aacagggcca tccggcccga cgaggccggc ctggtctacg acgcgctgct 12540 tcagcgcgtg gctcgttaca acagcggcaa cgtgcagacc aacctggacc ggctggtggg 12600 ggatgtgcgc gaggccgtgg cgcagcgtga gcgcgcgcag cagcagggca acctgggctc 12660 catggttgca ctaaacgcct tcctgagtac acagcccgcc aacgtgccgc ggggacagga 12720 ggactacacc aactttgtga gcgcactgcg gctaatggtg actgagacac cgcaaagtga 12780 ggtgtaccag tctgggccag actatttttt ccagaccagt agacaaggcc tgcagaccgt 12840 aaacctgagc caggctttca aaaacttgca ggggctgtgg ggggtgcggg ctcccacagg 12900 cgaccgcgcg accgtgtcta gcttgctgac gcccaactcg cgcctgttgc tgctgctaat 12960 agcgcccttc acggacagtg gcagcgtgtc ccgggacaca tacctaggtc acttgctgac 13020 actgtaccgc gaggccatag gtcaggcgca tgtggacgag catactttcc aggagattac 13080 aagtgtcagc cgcgcgctgg ggcaggagga cacgggcagc ctggaggcaa ccctaaacta 13140 cctgctgacc aaccggcggc agaagatccc ctcgttgcac agtttaaaca gcgaggagga 13200 gcgcattttg cgctacgtgc agcagagcgt gagccttaac ctgatgcgcg acggggtaac 13260 gcccagcgtg gcgctggaca tgaccgcgcg caacatggaa ccgggcatgt atgcctcaaa 13320 ccggccgttt atcaaccgcc taatggacta cttgcatcgc gcggccgccg tgaaccccga 13380 gtatttcacc aatgccatct tgaacccgca ctggctaccg ccccctggtt tctacaccgg 13440 gggattcgag gtgcccgagg gtaacgatgg attcctctgg gacgacatag acgacagcgt 13500 gttttccccg caaccgcaga ccctgctaga gttgcaacag cgcgagcagg cagaggcggc 13560 gctgcgaaag gaaagcttcc gcaggccaag cagcttgtcc gatctaggcg ctgcggcccc 13620 gcggtcagat gctagtagcc catttccaag cttgataggg tctcttacca gcactcgcac 13680 cacccgcccg cgcctgctgg gcgaggagga gtacctaaac aactcgctgc tgcagccgca 13740 gcgcgaaaaa aacctgcctc cggcatttcc caacaacggg atagagagcc tagtggacaa 13800 gatgagtaga tggaagacgt acgcgcagga gcacagggac gtgccaggcc cgcgcccgcc 13860 cacccgtcgt caaaggcacg accgtcagcg gggtctggtg tgggaggacg atgactcggc 13920 agacgacagc agcgtcctgg atttgggagg gagtggcaac ccgtttgcgc accttcgccc 13980 caggctgggg agaatgtttt aaaaaaaaaa aagcatgatg caaaataaaa aactcaccaa 14040 ggccatggca ccgagcgttg gttttcttgt attcccctta gtatgcggcg cgcggcgatg 14100 tatgaggaag gtcctcctcc ctcctacgag agtgtggtga gcgcggcgcc agtggcggcg 14160 gcgctgggtt ctcccttcga tgctcccctg gacccgccgt ttgtgcctcc gcggtacctg 14220 cggcctaccg gggggagaaa cagcatccgt tactctgagt tggcacccct attcgacacc 14280 acccgtgtgt acctggtgga caacaagtca acggatgtgg catccctgaa ctaccagaac 14340 gaccacagca actttctgac cacggtcatt caaaacaatg actacagccc gggggaggca 14400 agcacacaga ccatcaatct tgacgaccgg tcgcactggg gcggcgacct gaaaaccatc 14460 ctgcatacca acatgccaaa tgtgaacgag ttcatgttta ccaataagtt taaggcgcgg 14520 gtgatggtgt cgcgcttgcc tactaaggac aatcaggtgg agctgaaata cgagtgggtg 14580 gagttcacgc tgcccgaggg caactactcc gagaccatga ccatagacct tatgaacaac 14640 gcgatcgtgg agcactactt gaaagtgggc agacagaacg gggttctgga aagcgacatc 14700 ggggtaaagt ttgacacccg caacttcaga ctggggtttg accccgtcac tggtcttgtc 14760 atgcctgggg tatatacaaa cgaagccttc catccagaca tcattttgct gccaggatgc 14820 ggggtggact tcacccacag ccgcctgagc aacttgttgg gcatccgcaa gcggcaaccc 14880 ttccaggagg gctttaggat cacctacgat gatctggagg gtggtaacat tcccgcactg 14940 ttggatgtgg acgcctacca ggcgagcttg aaagatgaca ccgaacaggg cgggggtggc 15000 gcaggcggca gcaacagcag tggcagcggc gcggaagaga actccaacgc ggcagccgcg 15060 gcaatgcagc cggtggagga catgaacgat catgccattc gcggcgacac ctttgccaca 15120 cgggctgagg agaagcgcgc tgaggccgaa gcagcggccg aagctgccgc ccccgctgcg 15180 caacccgagg tcgagaagcc tcagaagaaa ccggtgatca aacccctgac agaggacagc 15240 aagaaacgca gttacaacct aataagcaat gacagcacct tcacccagta ccgcagctgg 15300 taccttgcat acaactacgg cgaccctcag accggaatcc gctcatggac cctgctttgc 15360 actcctgacg taacctgcgg ctcggagcag gtctactggt cgttgccaga catgatgcaa 15420 gaccccgtga ccttccgctc cacgcgccag atcagcaact ttccggtggt gggcgccgag 15480 ctgttgcccg tgcactccaa gagcttctac aacgaccagg ccgtctactc ccaactcatc 15540 cgccagttta cctctctgac ccacgtgttc aatcgctttc ccgagaacca gattttggcg 15600 cgcccgccag cccccaccat caccaccgtc agtgaaaacg ttcctgctct cacagatcac 15660 gggacgctac cgctgcgcaa cagcatcgga ggagtccagc gagtgaccat tactgacgcc 15720 agacgccgca cctgccccta cgtttacaag gccctgggca tagtctcgcc gcgcgtccta 15780 tcgagccgca ctttttgagc aagcatgtcc atccttatat cgcccagcaa taacacaggc 15840 tggggcctgc gcttcccaag caagatgttt ggcggggcca agaagcgctc cgaccaacac 15900 ccagtgcgcg tgcgcgggca ctaccgcgcg ccctggggcg cgcacaaacg cggccgcact 15960 gggcgcacca ccgtcgatga cgccatcgac gcggtggtgg aggaggcgcg caactacacg 16020 cccacgccgc caccagtgtc cacagtggac gcggccattc agaccgtggt gcgcggagcc 16080 cggcgctatg ctaaaatgaa gagacggcgg aggcgcgtag cacgtcgcca ccgccgccga 16140 cccggcactg ccgcccaacg cgcggcggcg gccctgctta accgcgcacg tcgcaccggc 16200 cgacgggcgg ccatgcgggc cgctcgaagg ctggccgcgg gtattgtcac tgtgcccccc 16260 aggtccaggc gacgagcggc cgccgcagca gccgcggcca ttagtgctat gactcagggt 16320 cgcaggggca acgtgtattg ggtgcgcgac tcggttagcg gcctgcgcgt gcccgtgcgc 16380 acccgccccc cgcgcaacta gattgcaaga aaaaactact tagactcgta ctgttgtatg 16440 tatccagcgg cggcggcgcg caacgaagct atgtccaagc gcaaaatcaa agaagagatg 16500 ctccaggtca tcgcgccgga gatctatggc cccccgaaga aggaagagca ggattacaag 16560 ccccgaaagc taaagcgggt caaaaagaaa aagaaagatg atgatgatga acttgacgac 16620 gaggtggaac tgctgcacgc taccgcgccc aggcgacggg tacagtggaa aggtcgacgc 16680 gtaaaacgtg ttttgcgacc cggcaccacc gtagtcttta cgcccggtga gcgctccacc 16740 cgcacctaca agcgcgtgta tgatgaggtg tacggcgacg aggacctgct tgagcaggcc 16800 aacgagcgcc tcggggagtt tgcctacgga aagcggcata aggacatgct ggcgttgccg 16860 ctggacgagg gcaacccaac acctagccta aagcccgtaa cactgcagca ggtgctgccc 16920 gcgcttgcac cgtccgaaga aaagcgcggc ctaaagcgcg agtctggtga cttggcaccc 16980 accgtgcagc tgatggtacc caagcgccag cgactggaag atgtcttgga aaaaatgacc 17040 gtggaacctg ggctggagcc cgaggtccgc gtgcggccaa tcaagcaggt ggcgccggga 17100 ctgggcgtgc agaccgtgga cgttcagata cccactacca gtagcaccag tattgccacc 17160 gccacagagg gcatggagac acaaacgtcc ccggttgcct cagcggtggc ggatgccgcg 17220 gtgcaggcgg tcgctgcggc cgcgtccaag acctctacgg aggtgcaaac ggacccgtgg 17280 atgtttcgcg tttcagcccc ccggcgcccg cgccgttcga ggaagtacgg cgccgccagc 17340 gcgctactgc ccgaatatgc cctacatcct tccattgcgc ctacccccgg ctatcgtggc 17400 tacacctacc gccccagaag acgagcaact acccgacgcc gaaccaccac tggaacccgc 17460 cgccgccgtc gccgtcgcca gcccgtgctg gccccgattt ccgtgcgcag ggtggctcgc 17520 gaaggaggca ggaccctggt gctgccaaca gcgcgctacc accccagcat cgtttaaaag 17580 ccggtctttg tggttcttgc agatatggcc ctcacctgcc gcctccgttt cccggtgccg 17640 ggattccgag gaagaatgca ccgtaggagg ggcatggccg gccacggcct gacgggcggc 17700 atgcgtcgtg cgcaccaccg gcggcggcgc gcgtcgcacc gtcgcatgcg cggcggtatc 17760 ctgcccctcc ttattccact gatcgccgcg gcgattggcg ccgtgcccgg aattgcatcc 17820 gtggccttgc aggcgcagag acactgatta aaaacaagtt gcatgtggaa aaatcaaaat 17880 aaaaagtctg gactctcacg ctcgcttggt cctgtaacta ttttgtagaa tggaagacat 17940 caactttgcg tctctggccc cgcgacacgg ctcgcgcccg ttcatgggaa actggcaaga 18000 tatcggcacc agcaatatga gcggtggcgc cttcagctgg ggctcgctgt ggagcggcat 18060 taaaaatttc ggttccaccg ttaagaacta tggcagcaag gcctggaaca gcagcacagg 18120 ccagatgctg agggataagt tgaaagagca aaatttccaa caaaaggtgg tagatggcct 18180 ggcctctggc attagcgggg tggtggacct ggccaaccag gcagtgcaaa ataagattaa 18240 cagtaagctt gatccccgcc ctcccgtaga ggagcctcca ccggccgtgg agacagtgtc 18300 tccagagggg cgtggcgaaa agcgtccgcg ccccgacagg gaagaaactc tggtgacgca 18360 aatagacgag cctccctcgt acgaggaggc actaaagcaa ggcctgccca ccacccgtcc 18420 catcgcgccc atggctaccg gagtgctggg ccagcacaca cccgtaacgc tggacctgcc 18480 tccccccgcc gacacccagc agaaacctgt gctgccaggc ccgaccgccg ttgttgtaac 18540 ccgtcctagc cgcgcgtccc tgcgccgcgc cgccagcggt ccgcgatcgt tgcggcccgt 18600 agccagtggc aactggcaaa gcacactgaa cagcatcgtg ggtctggggg tgcaatccct 18660 gaagcgccga cgatgcttct gatagctaac gtgtcgtatg tgtgtcatgt atgcgtccat 18720 gtcgccgcca gaggagctgc tgagccgccg cgcgcccgct ttccaagatg gctacccctt 18780 cgatgatgcc gcagtggtct tacatgcaca tctcgggcca ggacgcctcg gagtacctga 18840 gccccgggct ggtgcagttt gcccgcgcca ccgagacgta cttcagcctg aataacaagt 18900 ttagaaaccc cacggtggcg cctacgcacg acgtgaccac agaccggtcc cagcgtttga 18960 cgctgcggtt catccctgtg gaccgtgagg atactgcgta ctcgtacaag gcgcggttca 19020 ccctagctgt gggtgataac cgtgtgctgg acatggcttc cacgtacttt gacatccgcg 19080 gcgtgctgga caggggccct acttttaagc cctactctgg cactgcctac aacgccctgg 19140 ctcccaaggg tgccccaaat ccttgcgaat gggatgaagc tgctactgct cttgaaataa 19200 acctagaaga agaggacgat gacaacgaag acgaagtaga cgagcaagct gagcagcaaa 19260 aaactcacgt atttgggcag gcgccttatt ctggtataaa tattacaaag gagggtattc 19320 aaataggtgt cgaaggtcaa acacctaaat atgccgataa aacatttcaa cctgaacctc 19380 aaataggaga atctcagtgg tacgaaacag aaattaatca tgcagctggg agagtcctaa 19440 aaaagactac cccaatgaaa ccatgttacg gttcatatgc aaaacccaca aatgaaaatg 19500 gagggcaagg cattcttgta aagcaacaaa atggaaagct agaaagtcaa gtggaaatgc 19560 aatttttctc aactactgag gcagccgcag gcaatggtga taacttgact cctaaagtgg 19620 tattgtacag tgaagatgta gatatagaaa ccccagacac tcatatttct tacatgccca 19680 ctattaagga aggtaactca cgagaactaa tgggccaaca atctatgccc aacaggccta 19740 attacattgc ttttagggac aattttattg gtctaatgta ttacaacagc acgggtaata 19800 tgggtgttct ggcgggccaa gcatcgcagt tgaatgctgt tgtagatttg caagacagaa 19860 acacagagct ttcataccag cttttgcttg attccattgg tgatagaacc aggtactttt 19920 ctatgtggaa tcaggctgtt gacagctatg atccagatgt tagaattatt gaaaatcatg 19980 gaactgaaga tgaacttcca aattactgct ttccactggg aggtgtgatt aatacagaga 20040 ctcttaccaa ggtaaaacct aaaacaggtc aggaaaatgg atgggaaaaa gatgctacag 20100 aattttcaga taaaaatgaa ataagagttg gaaataattt tgccatggaa atcaatctaa 20160 atgccaacct gtggagaaat ttcctgtact ccaacatagc gctgtatttg cccgacaagc 20220 taaagtacag tccttccaac gtaaaaattt ctgataaccc aaacacctac gactacatga 20280 acaagcgagt ggtggctccc gggctagtgg actgctacat taaccttgga gcacgctggt 20340 cccttgacta tatggacaac gtcaacccat ttaaccacca ccgcaatgct ggcctgcgct 20400 accgctcaat gttgctgggc aatggtcgct atgtgccctt ccacatccag gtgcctcaga 20460 agttctttgc cattaaaaac ctccttctcc tgccgggctc atacacctac gagtggaact 20520 tcaggaagga tgttaacatg gttctgcaga gctccctagg aaatgaccta agggttgacg 20580 gagccagcat taagtttgat agcatttgcc tttacgccac cttcttcccc atggcccaca 20640 acaccgcctc cacgcttgag gccatgctta gaaacgacac caacgaccag tcctttaacg 20700 actatctctc cgccgccaac atgctctacc ctatacccgc caacgctacc aacgtgccca 20760 tatccatccc ctcccgcaac tgggcggctt tccgcggctg ggccttcacg cgccttaaga 20820 ctaaggaaac cccatcactg ggctcgggct acgaccctta ttacacctac tctggctcta 20880 taccctacct agatggaacc ttttacctca accacacctt taagaaggtg gccattacct 20940 ttgactcttc tgtcagctgg cctggcaatg accgcctgct tacccccaac gagtttgaaa 21000 ttaagcgctc agttgacggg gagggttaca acgttgccca gtgtaacatg accaaagact 21060 ggttcctggt acaaatgcta gctaactata acattggcta ccagggcttc tatatcccag 21120 agagctacaa ggaccgcatg tactccttct ttagaaactt ccagcccatg agccgtcagg 21180 tggtggatga tactaaatac aaggactacc aacaggtggg catcctacac caacacaaca 21240 actctggatt tgttggctac cttgccccca ccatgcgcga aggacaggcc taccctgcta 21300 acttccccta tccgcttata ggcaagaccg cagttgacag cattacccag aaaaagtttc 21360 tttgcgatcg caccctttgg cgcatcccat tctccagtaa ctttatgtcc atgggcgcac 21420 tcacagacct gggccaaaac cttctctacg ccaactccgc ccacgcgcta gacatgactt 21480 ttgaggtgga tcccatggac gagcccaccc ttctttatgt tttgtttgaa gtctttgacg 21540 tggtccgtgt gcaccagccg caccgcggcg tcatcgaaac cgtgtacctg cgcacgccct 21600 tctcggccgg caacgccaca acataaagaa gcaagcaaca tcaacaacag ctgccgccat 21660 gggctccagt gagcaggaac tgaaagccat tgtcaaagat cttggttgtg ggccatattt 21720 tttgggcacc tatgacaagc gctttccagg ctttgtttct ccacacaagc tcgcctgcgc 21780 catagtcaat acggccggtc gcgagactgg gggcgtacac tggatggcct ttgcctggaa 21840 cccgcactca aaaacatgct acctctttga gccctttggc ttttctgacc agcgactcaa 21900 gcaggtttac cagtttgagt acgagtcact cctgcgccgt agcgccattg cttcttcccc 21960 cgaccgctgt ataacgctgg aaaagtccac ccaaagcgta caggggccca actcggccgc 22020 ctgtggacta ttctgctgca tgtttctcca cgcctttgcc aactggcccc aaactcccat 22080 ggatcacaac cccaccatga accttattac cggggtaccc aactccatgc tcaacagtcc 22140 ccaggtacag cccaccctgc gtcgcaacca ggaacagctc tacagcttcc tggagcgcca 22200 ctcgccctac ttccgcagcc acagtgcgca gattaggagc gccacttctt tttgtcactt 22260 gaaaaacatg taaaaataat gtactagaga cactttcaat aaaggcaaat gcttttattt 22320 gtacactctc gggtgattat ttacccccac ccttgccgtc tgcgccgttt aaaaatcaaa 22380 ggggttctgc cgcgcatcgc tatgcgccac tggcagggac acgttgcgat actggtgttt 22440 agtgctccac ttaaactcag gcacaaccat ccgcggcagc tcggtgaagt tttcactcca 22500 caggctgcgc accatcacca acgcgtttag caggtcgggc gccgatatct tgaagtcgca 22560 gttggggcct ccgccctgcg cgcgcgagtt gcgatacaca gggttgcagc actggaacac 22620 tatcagcgcc gggtggtgca cgctggccag cacgctcttg tcggagatca gatccgcgtc 22680 caggtcctcc gcgttgctca gggcgaacgg agtcaacttt ggtagctgcc ttcccaaaaa 22740 gggcgcgtgc ccaggctttg agttgcactc gcaccgtagt ggcatcaaaa ggtgaccgtg 22800 cccggtctgg gcgttaggat acagcgcctg cataaaagcc ttgatctgct taaaagccac 22860 ctgagccttt gcgccttcag agaagaacat gccgcaagac ttgccggaaa actgattggc 22920 cggacaggcc gcgtcgtgca cgcagcacct tgcgtcggtg ttggagatct gcaccacatt 22980 tcggccccac cggttcttca cgatcttggc cttgctagac tgctccttca gcgcgcgctg 23040 cccgttttcg ctcgtcacat ccatttcaat cacgtgctcc ttatttatca taatgcttcc 23100 gtgtagacac ttaagctcgc cttcgatctc agcgcagcgg tgcagccaca acgcgcagcc 23160 cgtgggctcg tgatgcttgt aggtcacctc tgcaaacgac tgcaggtacg cctgcaggaa 23220 tcgccccatc atcgtcacaa aggtcttgtt gctggtgaag gtcagctgca acccgcggtg 23280 ctcctcgttc agccaggtct tgcatacggc cgccagagct tccacttggt caggcagtag 23340 tttgaagttc gcctttagat cgttatccac gtggtacttg tccatcagcg cgcgcgcagc 23400 ctccatgccc ttctcccacg cagacacgat cggcacactc agcgggttca tcaccgtaat 23460 ttcactttcc gcttcgctgg gctcttcctc ttcctcttgc gtccgcatac cacgcgccac 23520 tgggtcgtct tcattcagcc gccgcactgt gcgcttacct cctttgccat gcttgattag 23580 caccggtggg ttgctgaaac ccaccatttg tagcgccaca tcttctcttt cttcctcgct 23640 gtccacgatt acctctggtg atggcgggcg ctcgggcttg ggagaagggc gcttcttttt 23700 cttcttgggc gcaatggcca aatccgccgc cgaggtcgat ggccgcgggc tgggtgtgcg 23760 cggcaccagc gcgtcttgtg atgagtcttc ctcgtcctcg gactcgatac gccgcctcat 23820 ccgctttttt gggggcgccc ggggaggcgg cggcgacggg gacggggacg acacgtcctc 23880 catggttggg ggacgtcgcg ccgcaccgcg tccgcgctcg ggggtggttt cgcgctgctc 23940 ctcttcccga ctggccattt ccttctccta taggcagaaa aagatcatgg agtcagtcga 24000 gaagaaggac agcctaaccg ccccctctga gttcgccacc accgcctcca ccgatgccgc 24060 caacgcgcct accaccttcc ccgtcgaggc acccccgctt gaggaggagg aagtgattat 24120 cgagcaggac ccaggttttg taagcgaaga cgacgaggac cgctcagtac caacagagga 24180 taaaaagcaa gaccaggaca acgcagaggc aaacgaggaa caagtcgggc ggggggacga 24240 aaggcatggc gactacctag atgtgggaga cgacgtgctg ttgaagcatc tgcagcgcca 24300 gtgcgccatt atctgcgacg cgttgcaaga gcgcagcgat gtgcccctcg ccatagcgga 24360 tgtcagcctt gcctacgaac gccacctatt ctcaccgcgc gtacccccca aacgccaaga 24420 aaacggcaca tgcgagccca acccgcgcct caacttctac cccgtatttg ccgtgccaga 24480 ggtgcttgcc acctatcaca tctttttcca aaactgcaag atacccctat cctgccgtgc 24540 caaccgcagc cgagcggaca agcagctggc cttgcggcag ggcgctgtca tacctgatat 24600 cgcctcgctc aacgaagtgc caaaaatctt tgagggtctt ggacgcgacg agaagcgcgc 24660 ggcaaacgct ctgcaacagg aaaacagcga aaatgaaagt cactctggag tgttggtgga 24720 actcgagggt gacaacgcgc gcctagccgt actaaaacgc agcatcgagg tcacccactt 24780 tgcctacccg gcacttaacc taccccccaa ggtcatgagc acagtcatga gtgagctgat 24840 cgtgcgccgt gcgcagcccc tggagaggga tgcaaatttg caagaacaaa cagaggaggg 24900 cctacccgca gttggcgacg agcagctagc gcgctggctt caaacgcgcg agcctgccga 24960 cttggaggag cgacgcaaac taatgatggc cgcagtgctc gttaccgtgg agcttgagtg 25020 catgcagcgg ttctttgctg acccggagat gcagcgcaag ctagaggaaa cattgcacta 25080 cacctttcga cagggctacg tacgccaggc ctgcaagatc tccaacgtgg agctctgcaa 25140 cctggtctcc taccttggaa ttttgcacga aaaccgcctt gggcaaaacg tgcttcattc 25200 cacgctcaag ggcgaggcgc gccgcgacta cgtccgcgac tgcgtttact tatttctatg 25260 ctacacctgg cagacggcca tgggcgtttg gcagcagtgc ttggaggagt gcaacctcaa 25320 ggagctgcag aaactgctaa agcaaaactt gaaggaccta tggacggcct tcaacgagcg 25380 ctccgtggcc gcgcacctgg cggacatcat tttccccgaa cgcctgctta aaaccctgca 25440 acagggtctg ccagacttca ccagtcaaag catgttgcag aactttagga actttatcct 25500 agagcgctca ggaatcttgc ccgccacctg ctgtgcactt cctagcgact ttgtgcccat 25560 taagtaccgc gaatgccctc cgccgctttg gggccactgc taccttctgc agctagccaa 25620 ctaccttgcc taccactctg acataatgga agacgtgagc ggtgacggtc tactggagtg 25680 tcactgtcgc tgcaacctat gcaccccgca ccgctccctg gtttgcaatt cgcagctgct 25740 taacgaaagt caaattatcg gtacctttga gctgcagggt ccctcgcctg acgaaaagtc 25800 cgcggctccg gggttgaaac tcactccggg gctgtggacg tcggcttacc ttcgcaaatt 25860 tgtacctgag gactaccacg cccacgagat taggttctac gaagaccaat cccgcccgcc 25920 taatgcggag cttaccgcct gcgtcattac ccagggccac attcttggcc aattgcaagc 25980 catcaacaaa gcccgccaag agtttctgct acgaaaggga cggggggttt acttggaccc 26040 ccagtccggc gaggagctca acccaatccc cccgccgccg cagccctatc agcagcagcc 26100 gcgggccctt gcttcccagg atggcaccca aaaagaagct gcagctgccg ccgccaccca 26160 cggacgagga ggaatactgg gacagtcagg cagaggaggt tttggacgag gaggaggagg 26220 acatgatgga agactgggag agcctagacg aggaagcttc cgaggtcgaa gaggtgtcag 26280 acgaaacacc gtcaccctcg gtcgcattcc cctcgccggc gccccagaaa tcggcaaccg 26340 gttccagcat ggctacaacc tccgctcctc aggcgccgcc ggcactgccc gttcgccgac 26400 ccaaccgtag atgggacacc actggaacca gggccggtaa gtccaagcag ccgccgccgt 26460 tagcccaaga gcaacaacag cgccaaggct accgctcatg gcgcgggcac aagaacgcca 26520 tagttgcttg cttgcaagac tgtgggggca acatctcctt cgcccgccgc tttcttctct 26580 accatcacgg cgtggccttc ccccgtaaca tcctgcatta ctaccgtcat ctctacagcc 26640 catactgcac cggcggcagc ggcagcaaca gcagcggcca cacagaagca aaggcgaccg 26700 gatagcaaga ctctgacaaa gcccaagaaa tccacagcgg cggcagcagc aggaggagga 26760 gcgctgcgtc tggcgcccaa cgaacccgta tcgacccgcg agcttagaaa caggattttt 26820 cccactctgt atgctatatt tcaacagagc aggggccaag aacaagagct gaaaataaaa 26880 aacaggtctc tgcgatccct cacccgcagc tgcctgtatc acaaaagcga agatcagctt 26940 cggcgcacgc tggaagacgc ggaggctctc ttcagtaaat actgcgcgct gactcttaag 27000 gactagtttc gcgccctttc tcaaatttaa gcgcgaaaac tacgtcatct ccagcggcca 27060 cacccggcgc cagcacctgt tgtcagcgcc attatgagca aggaaattcc cacgccctac 27120 atgtggagtt accagccaca aatgggactt gcggctggag ctgcccaaga ctactcaacc 27180 cgaataaact acatgagcgc gggaccccac atgatatccc gggtcaacgg aatacgcgcc 27240 caccgaaacc gaattctcct ggaacaggcg gctattacca ccacacctcg taataacctt 27300 aatccccgta gttggcccgc tgccctggtg taccaggaaa gtcccgctcc caccactgtg 27360 gtacttccca gagacgccca ggccgaagtt cagatgacta actcaggggc gcagcttgcg 27420 ggcggctttc gtcacagggt gcggtcgccc gggcagggta taactcacct gacaatcaga 27480 gggcgaggta ttcagctcaa cgacgagtcg gtgagctcct cgcttggtct ccgtccggac 27540 gggacatttc agatcggcgg cgccggccgc tcttcattca cgcctcgtca ggcaatccta 27600 actctgcaga cctcgtcctc tgagccgcgc tctggaggca ttggaactct gcaatttatt 27660 gaggagtttg tgccatcggt ctactttaac cccttctcgg gacctcccgg ccactatccg 27720 gatcaattta ttcctaactt tgacgcggta aaggactcgg cggacggcta cgactgaatg 27780 ttaagtggag aggcagagca actgcgcctg aaacacctgg tccactgtcg ccgccacaag 27840 tgctttgccc gcgactccgg tgagttttgc tactttgaat tgcccgagga tcatatcgag 27900 ggcccggcgc acggcgtccg gcttaccgcc cagggagagc ttgcccgtag cctgattcgg 27960 gagtttaccc agcgccccct gctagttgag cgggacaggg gaccctgtgt tctcactgtg 28020 atttgcaact gtcctaaccc tggattacat caagatcctc tagttaatgt caggtcgcct 28080 aagtcgatta actagagtac ccggggatct tattcccttt aactaataaa aaaaaataat 28140 aaagcatcac ttacttaaaa tcagttagca aatttctgtc cagtttattc agcagcacct 28200 ccttgccctc ctcccagctc tggtattgca gcttcctcct ggctgcaaac tttctccaca 28260 atctaaatgg aatgtcagtt tcctcctgtt cctgtccatc cgcacccact atcttcatgt 28320 tgttgcagat gaagcgcgca agaccgtctg aagatacctt caaccccgtg tatccatatg 28380 acacggaaac cggtcctcca actgtgcctt ttcttactcc tccctttgta tcccccaatg 28440 ggtttcaaga gagtccccct ggggtactct ctttgcgcct atccgaacct ctagttacct 28500 ccaatggcat gcttgcgctc aaaatgggca acggcctctc tctggacgag gccggcaacc 28560 ttacctccca aaatgtaacc actgtgagcc cacctctcaa aaaaaccaag tcaaacataa 28620 acctggaaat atctgcaccc ctcacagtta cctcagaagc cctaactgtg gctgccgccg 28680 cacctctaat ggtcgcgggc aacacactca ccatgcaatc acaggccccg ctaaccgtgc 28740 acgactccaa acttagcatt gccacccaag gacccctcac agtgtcagaa ggaaagctag 28800 ccctgcaaac atcaggcccc ctcaccacca ccgatagcag tacccttact atcactgcct 28860 caccccctct aactactgcc actggtagct tgggcattga cttgaaagag cccatttata 28920 cacaaaatgg aaaactagga ctaaagtacg gggctccttt gcatgtaaca gacgacctaa 28980 acactttgac cgtagcaact ggtccaggtg tgactattaa taatacttcc ttgcaaacta 29040 aagttactgg agccttgggt tttgattcac aaggcaatat gcaacttaat gtagcaggag 29100 gactaaggat tgattctcaa aacagacgcc ttatacttga tgttagttat ccgtttgatg 29160 ctcaaaacca actaaatcta agactaggac agggccctct ttttataaac tcagcccaca 29220 acttggatat taactacaac aaaggccttt acttgtttac agcttcaaac aattccaaaa 29280 agcttgaggt taacctaagc actgccaagg ggttgatgtt tgacgctaca gccatagcca 29340 ttaatgcagg agatgggctt gaatttggtt cacctaatgc accaaacaca aatcccctca 29400 aaacaaaaat tggccatggc ctagaatttg attcaaacaa ggctatggtt cctaaactag 29460 gaactggcct tagttttgac agcacaggtg ccattacagt aggaaacaaa aataatgata 29520 agctaacttt gtggaccaca ccagctccat ctcctaactg tagactaaat gcagagaaag 29580 atgctaaact cactttggtc ttaacaaaat gtggcagtca aatacttgct acagtttcag 29640 ttttggctgt taaaggcagt ttggctccaa tatctggaac agttcaaagt gctcatctta 29700 ttataagatt tgacgaaaat ggagtgctac taaacaattc cttcctggac ccagaatatt 29760 ggaactttag aaatggagat cttactgaag gcacagccta tacaaacgct gttggattta 29820 tgcctaacct atcagcttat ccaaaatctc acggtaaaac tgccaaaagt aacattgtca 29880 gtcaagttta cttaaacgga gacaaaacta aacctgtaac actaaccatt acactaaacg 29940 gtacacagga aacaggagac acaactccaa gtgcatactc tatgtcattt tcatgggact 30000 ggtctggcca caactacatt aatgaaatat ttgccacatc ctcttacact ttttcataca 30060 ttgcccaaga ataaagaatc gtttgtgtta tgtttcaacg tgtttatttt tcaattgcag 30120 aaaatttcaa gtcatttttc attcagtagt atagccccac caccacatag cttatacaga 30180 tcaccgtacc ttaatcaaac tcacagaacc ctagtattca acctgccacc tccctcccaa 30240 cacacagagt acacagtcct ttctccccgg ctggccttaa aaagcatcat atcatgggta 30300 acagacatat tcttaggtgt tatattccac acggtttcct gtcgagccaa acgctcatca 30360 gtgatattaa taaactcccc gggcagctca cttaagttca tgtcgctgtc cagctgctga 30420 gccacaggct gctgtccaac ttgcggttgc ttaacgggcg gcgaaggaga agtccacgcc 30480 tacatggggg tagagtcata atcgtgcatc aggatagggc ggtggtgctg cagcagcgcg 30540 cgaataaact gctgccgccg ccgctccgtc ctgcaggaat acaacatggc agtggtctcc 30600 tcagcgatga ttcgcaccgc ccgcagcata aggcgccttg tcctccgggc acagcagcgc 30660 accctgatct cacttaaatc agcacagtaa ctgcagcaca gcaccacaat attgttcaaa 30720 atcccacagt gcaaggcgct gtatccaaag ctcatggcgg ggaccacaga acccacgtgg 30780 ccatcatacc acaagcgcag gtagattaag tggcgacccc tcataaacac gctggacata 30840 aacattacct cttttggcat gttgtaattc accacctccc ggtaccatat aaacctctga 30900 ttaaacatgg cgccatccac caccatccta aaccagctgg ccaaaacctg cccgccggct 30960 atacactgca gggaaccggg actggaacaa tgacagtgga gagcccagga ctcgtaacca 31020 tggatcatca tgctcgtcat gatatcaatg ttggcacaac acaggcacac gtgcatacac 31080 ttcctcagga ttacaagctc ctcccgcgtt agaaccatat cccagggaac aacccattcc 31140 tgaatcagcg taaatcccac actgcaggga agacctcgca cgtaactcac gttgtgcatt 31200 gtcaaagtgt tacattcggg cagcagcgga tgatcctcca gtatggtagc gcgggtttct 31260 gtctcaaaag gaggtagacg atccctactg tacggagtgc gccgagacaa ccgagatcgt 31320 gttggtcgta gtgtcatgcc aaatggaacg ccggacgtag tcatatttcc tgaagcaaaa 31380 ccaggtgcgg gcgtgacaaa cagatctgcg tctccggtct cgccgcttag atcgctctgt 31440 gtagtagttg tagtatatcc actctctcaa agcatccagg cgccccctgg cttcgggttc 31500 tatgtaaact ccttcatgcg ccgctgccct gataacatcc accaccgcag aataagccac 31560 acccagccaa cctacacatt cgttctgcga gtcacacacg ggaggagcgg gaagagctgg 31620 aagaaccatg tttttttttt tattccaaaa gattatccaa aacctcaaaa tgaagatcta 31680 ttaagtgaac gcgctcccct ccggtggcgt ggtcaaactc tacagccaaa gaacagataa 31740 tggcatttgt aagatgttgc acaatggctt ccaaaaggca aacggccctc acgtccaagt 31800 ggacgtaaag gctaaaccct tcagggtgaa tctcctctat aaacattcca gcaccttcaa 31860 ccatgcccaa ataattctca tctcgccacc ttctcaatat atctctaagc aaatcccgaa 31920 tattaagtcc ggccattgta aaaatctgct ccagagcgcc ctccaccttc agcctcaagc 31980 agcgaatcat gattgcaaaa attcaggttc ctcacagacc tgtataagat tcaaaagcgg 32040 aacattaaca aaaataccgc gatcccgtag gtcccttcgc agggccagct gaacataatc 32100 gtgcaggtct gcacggacca gcgcggccac ttccccgcca ggaaccatga caaaagaacc 32160 cacactgatt atgacacgca tactcggagc tatgctaacc agcgtagccc cgatgtaagc 32220 ttgttgcatg ggcggcgata taaaatgcaa ggtgctgctc aaaaaatcag gcaaagcctc 32280 gcgcaaaaaa gaaagcacat cgtagtcatg ctcatgcaga taaaggcagg taagctccgg 32340 aaccaccaca gaaaaagaca ccatttttct ctcaaacatg tctgcgggtt tctgcataaa 32400 cacaaaataa aataacaaaa aaacatttaa acattagaag cctgtcttac aacaggaaaa 32460 acaaccctta taagcataag acggactacg gccatgccgg cgtgaccgta aaaaaactgg 32520 tcaccgtgat taaaaagcac caccgacagc tcctcggtca tgtccggagt cataatgtaa 32580 gactcggtaa acacatcagg ttgattcaca tcggtcagtg ctaaaaagcg accgaaatag 32640 cccgggggaa tacatacccg caggcgtaga gacaacatta cagcccccat aggaggtata 32700 acaaaattaa taggagagaa aaacacataa acacctgaaa aaccctcctg cctaggcaaa 32760 atagcaccct cccgctccag aacaacatac agcgcttcca cagcggcagc cataacagtc 32820 agccttacca gtaaaaaaga aaacctatta aaaaaacacc actcgacacg gcaccagctc 32880 aatcagtcac agtgtaaaaa agggccaagt gcagagcgag tatatatagg actaaaaaat 32940 gacgtaacgg ttaaagtcca caaaaaacac ccagaaaacc gcacgcgaac ctacgcccag 33000 aaacgaaagc caaaaaaccc acaacttcct caaatcgtca cttccgtttt cccacgttac 33060 gtcacttccc attttaagaa aactacaatt cccaacacat acaagttact ccgccctaaa 33120 acctacgtca cccgccccgt tcccacgccc cgcgccacgt cacaaactcc accccctcat 33180 tatcatattg gcttcaatcc aaaataaggt atattattga tgatg 33225 <210> SEQ ID NO 95 <211> LENGTH: 34665 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 95 ttttggattg aagccaatat gataatgagg gggtggagtt tgtgacgtgg cgcggggcgt 60 gggaacgggg cgggtgacgt agtagtgtgg cggaagtgtg atgttgcaag tgtggcggaa 120 cacatgtaag cgacggatgt ggcaaaagtg acgtttttgg tgtgcgccgg tgttttgggc 180 gtaaccgagt aagatttggc cattttcgcg ggaaaactga ataagaggaa gtgaaatctg 240 aataattttg tgttactcat agcgcgtaat atttgtctag ggccgcgggg actttgaccg 300 tttacgtgga gactcgccca ggtgtttttc tcaggtgttt tccgcgttcc gggtcaaagt 360 tggcgtttta ttattatagt cagctgacgt gtagtgtatt tatacccggt gagttcctca 420 agaggccact cttgagtgcc agcgagtaga gttttctcct ccgagccgct ccgacaccgg 480 gactgaaaat gagacatatt atctgccacg gaggtgttat taccgaagaa atggccgcca 540 gtcttttgga ccagctgatc gaagaggtac tggctgataa tcttccacct cctagccatt 600 ttgaaccacc tacccttcac gaactgtatg atttagacgt gacggccccc gaagatccca 660 acgaggaggc ggtttcgcag atttttcccg actctgtaat gttggcggtg caggaaggga 720 ttgacttact cacttttccg ccggcgcccg gttctccgga gccgcctcac ctttcccggc 780 agcccgagca gccggagcag agagccttgg gtccggtttc tatgccaaac cttgtaccgg 840 aggtgatcga tcttacctgc cacgaggctg gctttccacc cagtgacgac gaggatgaag 900 agggtgagga gtttgtgtta gattatgtgg agcaccccgg gcacggttgc aggtcttgtc 960 attatcaccg gaggaatacg ggggacccag atattatgtg ttcgctttgc tatatgagga 1020 cctgtggcat gtttgtctac agtaagtgaa aattatgggc agtgggtgat agagtggtgg 1080 gtttggtgtg gtaatttttt ttttaatttt tacagttttg tggtttaaag aattttgtat 1140 tgtgattttt ttaaaaggtc ctgtgtctga acctgagcct gagcccgagc cagaaccgga 1200 gcctgcaaga cctacccgcc gtcctaaaat ggcgcctgct atcctgagac gcccgacatc 1260 acctgtgtct agagaatgca atagtagtac ggatagctgt gactccggtc cttctaacac 1320 acctcctgag atacacccgg tggtcccgct gtgccccatt aaaccagttg ccgtgagagt 1380 tggtgggcgt cgccaggctg tggaatgtat cgaggacttg cttaacgagc ctgggcaacc 1440 tttggacttg agctgtaaac gccccaggcc ataaggtgta aacctgtgat tgcgtgtgtg 1500 gttaacgcct ttgtttgctg aatgagttga tgtaagttta ataaagggtg agataatgtt 1560 taacttgcat ggcgtgttaa atggggcggg gcttaaaggg tatataatgc gccgtgggct 1620 aatcttggtt acatctgacc tcgtcgacgc caccatgtgt caccagcagc tcgtgattag 1680 ctggttcagc ctggtgtttc tggctagccc tctggtggcc atctgggagc tgaagaagga 1740 cgtgtacgtg gtggagctcg actggtaccc tgacgctccc ggcgagatgg tcgtgctgac 1800 ctgcgacacc cctgaggaag atggcatcac ctggaccctg gatcaaagct ccgaagtgct 1860 cggcagcggc aagacactca ccatccaggt gaaagagttc ggagacgccg gccagtacac 1920 ctgccacaaa ggcggcgagg tgctgtccca ttccctgctg ctgctgcaca agaaagagga 1980 tggcatctgg tccaccgaca tcctgaagga ccagaaggaa cccaagaaca agacctttct 2040 gagatgtgag gccaagaact acagcggcag gttcacctgc tggtggctga caacaatctc 2100 caccgacctg accttcagcg tcaagagcag caggggcagc agcgaccctc aaggcgtgac 2160 atgtggagcc gctaccctga gcgctgagag agtcaggggc gacaataagg agtacgagta 2220 ctccgtggaa tgccaggagg actccgcctg ccctgccgcc gaagagtccc tccctatcga 2280 agtgatggtt gatgccgtgc acaagctcaa gtatgagaat tacaccagca gctttttcat 2340 cagggacatc atcaagcccg acccccccaa aaacctccag ctgaaacccc tcaagaatag 2400 caggcaggtg gaggtctcct gggagtatcc tgacacctgg agcacccccc acagctactt 2460 ctccctgacc ttctgtgtgc aggtgcaggg caagagcaaa agggagaaga aggatagggt 2520 ctttaccgac aagaccagcg ccacagtgat ctgcaggaag aacgccagca tttccgtcag 2580 ggcccaggac aggtactaca gcagcagctg gtccgagtgg gctagcgtgc cttgttccgg 2640 cggcggagga tctggcggag gcggaagtgg cggagggggc tctagaaacc tccccgtggc 2700 cacacccgac cctggcatgt tcccctgcct ccaccacagc cagaacctgc tgagagccgt 2760 gagcaatatg ctgcagaagg ccaggcaaac cctggagttc tacccctgta cctccgagga 2820 gattgaccat gaggacatca caaaggacaa aaccagcacc gtggaggcct gtctccccct 2880 cgaactgacc aagaacgagt cctgcctgaa ctccagggag acatccttca tcaccaacgg 2940 ctcctgcctg gcctccagaa agaccagctt catgatggcc ctctgcctga gcagcatcta 3000 cgaggacctc aagatgtacc aggtggagtt taaaacaatg aacgccaagc tcctcatgga 3060 ccctaagagg cagattttcc tcgaccagaa tatgctggct gtcattgacg agctgatgca 3120 ggccctcaat ttcaactccg agaccgtccc ccagaagtcc tccctggaag agcccgactt 3180 ttacaagacc aagatcaagc tctgcatcct gctgcacgcc ttcagaatta gagccgtgac 3240 cattgacagg gtgatgagct acctcaacgc ctcctgatga ctcgagtcac caggcgcttt 3300 tccaagagaa ggtcatcaag actttggatt tttccacacc ggggcgcgct gcggctgctg 3360 ttgctttttt gagttttata aaggataaat ggagcgaaga aacccatctg agcggggggt 3420 acctgctgga ttttctggcc atgcatctgt ggagagcggt tgtgagacac aagaatcgcc 3480 tgctactgtt gtcttccgtc cgcccggcga taataccgac ggaggagcag cagcagcagc 3540 aggaggaagc caggcggcgg cggcaggagc agagcccatg gaacccgaga gccggcctgg 3600 accctcggga atgaatgttg tacaggtggc tgaactgtat ccagaactga gacgcatttt 3660 gacaattaca gaggatgggc aggggctaaa gggggtaaag agggagcggg gggcttgtga 3720 ggctacagag gaggctagga atctagcttt tagcttaatg accagacacc gtcctgagtg 3780 tattactttt caacagatca aggataattg cgctaatgag cttgatctgc tggcgcagaa 3840 gtattccata gagcagctga ccacttactg gctgcagcca ggggatgatt ttgaggaggc 3900 tattagggta tatgcaaagg tggcacttag gccagattgc aagtacaaga tcagcaaact 3960 tgtaaatatc aggaattgtt gctacatttc tgggaacggg gccgaggtgg agatagatac 4020 ggaggatagg gtggccttta gatgtagcat gataaatatg tggccggggg tgcttggcat 4080 ggacggggtg gttattatga atgtaaggtt tactggcccc aattttagcg gtacggtttt 4140 cctggccaat accaacctta tcctacacgg tgtaagcttc tatgggttta acaatacctg 4200 tgtggaagcc tggaccgatg taagggttcg gggctgtgcc ttttactgct gctggaaggg 4260 ggtggtgtgt cgccccaaaa gcagggcttc aattaagaaa tgcctctttg aaaggtgtac 4320 cttgggtatc ctgtctgagg gtaactccag ggtgcgccac aatgtggcct ccgactgtgg 4380 ttgcttcatg ctagtgaaaa gcgtggctgt gattaagcat aacatggtat gtggcaactg 4440 cgaggacagg gcctctcaga tgctgacctg ctcggacggc aactgtcacc tgctgaagac 4500 cattcacgta gccagccact ctcgcaaggc ctggccagtg tttgagcata acatactgac 4560 ccgctgttcc ttgcatttgg gtaacaggag gggggtgttc ctaccttacc aatgcaattt 4620 gagtcacact aagatattgc ttgagcccga gagcatgtcc aaggtgaacc tgaacggggt 4680 gtttgacatg accatgaaga tctggaaggt gctgaggtac gatgagaccc gcaccaggtg 4740 cagaccctgc gagtgtggcg gtaaacatat taggaaccag cctgtgatgc tggatgtgac 4800 cgaggagctg aggcccgatc acttggtgct ggcctgcacc cgcgctgagt ttggctctag 4860 cgatgaagat acagattgag gtactgaaat gtgtgggcgt ggcttaaggg tgggaaagaa 4920 tatataaggt gggggtctta tgtagttttg tatctgtttt gcagcagccg ccgccgccat 4980 gagcaccaac tcgtttgatg gaagcattgt gagctcatat ttgacaacgc gcatgccccc 5040 atgggccggg gtgcgtcaga atgtgatggg ctccagcatt gatggtcgcc ccgtcctgcc 5100 cgcaaactct actaccttga cctacgagac cgtgtctgga acgccgttgg agactgcagc 5160 ctccgccgcc gcttcagccg ctgcagccac cgcccgcggg attgtgactg actttgcttt 5220 cctgagcccg cttgcaagca gtgcagcttc ccgttcatcc gcccgcgatg acaagttgac 5280 ggctcttttg gcacaattgg attctttgac ccgggaactt aatgtcgttt ctcagcagct 5340 gttggatctg cgccagcagg tttctgccct gaaggcttcc tcccctccca atgcggttta 5400 aaacataaat aaaaaaccag actctgtttg gatttggatc aagcaagtgt cttgctgtct 5460 ttatttaggg gttttgcgcg cgcggtaggc ccgggaccag cggtctcggt cgttgagggt 5520 cctgtgtatt ttttccagga cgtggtaaag gtgactctgg atgttcagat acatgggcat 5580 aagcccgtct ctggggtgga ggtagcacca ctgcagagct tcatgctgcg gggtggtgtt 5640 gtagatgatc cagtcgtagc aggagcgctg ggcgtggtgc ctaaaaatgt ctttcagtag 5700 caagctgatt gccaggggca ggcccttggt gtaagtgttt acaaagcggt taagctggga 5760 tgggtgcata cgtggggata tgagatgcat cttggactgt atttttaggt tggctatgtt 5820 cccagccata tccctccggg gattcatgtt gtgcagaacc accagcacag tgtatccggt 5880 gcacttggga aatttgtcat gtagcttaga aggaaatgcg tggaagaact tggagacgcc 5940 cttgtgacct ccaagatttt ccatgcattc gtccataatg atggcaatgg gcccacgggc 6000 ggcggcctgg gcgaagatat ttctgggatc actaacgtca tagttgtgtt ccaggatgag 6060 atcgtcatag gccattttta caaagcgcgg gcggagggtg ccagactgcg gtataatggt 6120 tccatccggc ccaggggcgt agttaccctc acagatttgc atttcccacg ctttgagttc 6180 agatgggggg atcatgtcta cctgcggggc gatgaagaaa acggtttccg gggtagggga 6240 gatcagctgg gaagaaagca ggttcctgag cagctgcgac ttaccgcagc cggtgggccc 6300 gtaaatcaca cctattaccg gctgcaactg gtagttaaga gagctgcagc tgccgtcatc 6360 cctgagcagg ggggccactt cgttaagcat gtccctgact cgcatgtttt ccctgaccaa 6420 atccgccaga aggcgctcgc cgcccagcga tagcagttct tgcaaggaag caaagttttt 6480 caacggtttg agaccgtccg ccgtaggcat gcttttgagc gtttgaccaa gcagttccag 6540 gcggtcccac agctcggtca cctgctctac ggcatctcga tccagcatat ctcctcgttt 6600 cgcgggttgg ggcggctttc gctgtacggc agtagtcggt gctcgtccag acgggccagg 6660 gtcatgtctt tccacgggcg cagggtcctc gtcagcgtag tctgggtcac ggtgaagggg 6720 tgcgctccgg gctgcgcgct ggccagggtg cgcttgaggc tggtcctgct ggtgctgaag 6780 cgctgccggt cttcgccctg cgcgtcggcc aggtagcatt tgaccatggt gtcatagtcc 6840 agcccctccg cggcgtggcc cttggcgcgc agcttgccct tggaggaggc gccgcacgag 6900 gggcagtgca gacttttgag ggcgtagagc ttgggcgcga gaaataccga ttccggggag 6960 taggcatccg cgccgcaggc cccgcagacg gtctcgcatt ccacgagcca ggtgagctct 7020 ggccgttcgg ggtcaaaaac caggtttccc ccatgctttt tgatgcgttt cttacctctg 7080 gtttccatga gccggtgtcc acgctcggtg acgaaaaggc tgtccgtgtc cccgtataca 7140 gacttgagag gcctgtcctc gagcggtgtt ccgcggtcct cctcgtatag aaactcggac 7200 cactctgaga caaaggctcg cgtccaggcc agcacgaagg aggctaagtg ggaggggtag 7260 cggtcgttgt ccactagggg gtccactcgc tccagggtgt gaagacacat gtcgccctct 7320 tcggcatcaa ggaaggtgat tggtttgtag gtgtaggcca cgtgaccggg tgttcctgaa 7380 ggggggctat aaaagggggt gggggcgcgt tcgtcctcac tctcttccgc atcgctgtct 7440 gcgagggcca gctgttgggg tgagtactcc ctctgaaaag cgggcatgac ttctgcgcta 7500 agattgtcag tttccaaaaa cgaggaggat ttgatattca cctggcccgc ggtgatgcct 7560 ttgagggtgg ccgcatccat ctggtcagaa aagacaatct ttttgttgtc aagcttggtg 7620 gcaaacgacc cgtagagggc gttggacagc aacttggcga tggagcgcag ggtttggttt 7680 ttgtcgcgat cggcgcgctc cttggccgcg atgtttagct gcacgtattc gcgcgcaacg 7740 caccgccatt cgggaaagac ggtggtgcgc tcgtcgggca ccaggtgcac gcgccaaccg 7800 cggttgtgca gggtgacaag gtcaacgctg gtggctacct ctccgcgtag gcgctcgttg 7860 gtccagcaga ggcggccgcc cttgcgcgag cagaatggcg gtagggggtc tagctgcgtc 7920 tcgtccgggg ggtctgcgtc cacggtaaag accccgggca gcaggcgcgc gtcgaagtag 7980 tctatcttgc atccttgcaa gtctagcgcc tgctgccatg cgcgggcggc aagcgcgcgc 8040 tcgtatgggt tgagtggggg accccatggc atggggtggg tgagcgcgga ggcgtacatg 8100 ccgcaaatgt cgtaaacgta gaggggctct ctgagtattc caagatatgt agggtagcat 8160 cttccaccgc ggatgctggc gcgcacgtaa tcgtatagtt cgtgcgaggg agcgaggagg 8220 tcgggaccga ggttgctacg ggcgggctgc tctgctcgga agactatctg cctgaagatg 8280 gcatgtgagt tggatgatat ggttggacgc tggaagacgt tgaagctggc gtctgtgaga 8340 cctaccgcgt cacgcacgaa ggaggcgtag gagtcgcgca gcttgttgac cagctcggcg 8400 gtgacctgca cgtctagggc gcagtagtcc agggtttcct tgatgatgtc atacttatcc 8460 tgtccctttt ttttccacag ctcgcggttg aggacaaact cttcgcggtc tttccagtac 8520 tcttggatcg gaaacccgtc ggcctccgaa cggtaagagc ctagcatgta gaactggttg 8580 acggcctggt aggcgcagca tcccttttct acgggtagcg cgtatgcctg cgcggccttc 8640 cggagcgagg tgtgggtgag cgcaaaggtg tccctgacca tgactttgag gtactggtat 8700 ttgaagtcag tgtcgtcgca tccgccctgc tcccagagca aaaagtccgt gcgctttttg 8760 gaacgcggat ttggcagggc gaaggtgaca tcgttgaaga gtatctttcc cgcgcgaggc 8820 ataaagttgc gtgtgatgcg gaagggtccc ggcacctcgg aacggttgtt aattacctgg 8880 gcggcgagca cgatctcgtc aaagccgttg atgttgtggc ccacaatgta aagttccaag 8940 aagcgcggga tgcccttgat ggaaggcaat tttttaagtt cctcgtaggt gagctcttca 9000 ggggagctga gcccgtgctc tgaaagggcc cagtctgcaa gatgagggtt ggaagcgacg 9060 aatgagctcc acaggtcacg ggccattagc atttgcaggt ggtcgcgaaa ggtcctaaac 9120 tggcgaccta tggccatttt ttctggggtg atgcagtaga aggtaagcgg gtcttgttcc 9180 cagcggtccc atccaaggtt cgcggctagg tctcgcgcgg cagtcactag aggctcatct 9240 ccgccgaact tcatgaccag catgaagggc acgagctgct tcccaaaggc ccccatccaa 9300 gtataggtct ctacatcgta ggtgacaaag agacgctcgg tgcgaggatg cgagccgatc 9360 gggaagaact ggatctcccg ccaccaattg gaggagtggc tattgatgtg gtgaaagtag 9420 aagtccctgc gacgggccga acactcgtgc tggcttttgt aaaaacgtgc gcagtactgg 9480 cagcggtgca cgggctgtac atcctgcacg aggttgacct gacgaccgcg cacaaggaag 9540 cagagtggga atttgagccc ctcgcctggc gggtttggct ggtggtcttc tacttcggct 9600 gcttgtcctt gaccgtctgg ctgctcgagg ggagttacgg tggatcggac caccacgccg 9660 cgcgagccca aagtccagat gtccgcgcgc ggcggtcgga gcttgatgac aacatcgcgc 9720 agatgggagc tgtccatggt ctggagctcc cgcggcgtca ggtcaggcgg gagctcctgc 9780 aggtttacct cgcatagacg ggtcagggcg cgggctagat ccaggtgata cctaatttcc 9840 aggggctggt tggtggcggc gtcgatggct tgcaagaggc cgcatccccg cggcgcgact 9900 acggtaccgc gcggcgggcg gtgggccgcg ggggtgtcct tggatgatgc atctaaaagc 9960 ggtgacgcgg gcgagccccc ggaggtaggg ggggctccgg acccgccggg agagggggca 10020 ggggcacgtc ggcgccgcgc gcgggcagga gctggtgctg cgcgcgtagg ttgctggcga 10080 acgcgacgac gcggcggttg atctcctgaa tctggcgcct ctgcgtgaag acgacgggcc 10140 cggtgagctt gaacctgaaa gagagttcga cagaatcaat ttcggtgtcg ttgacggcgg 10200 cctggcgcaa aatctcctgc acgtctcctg agttgtcttg ataggcgatc tcggccatga 10260 actgctcgat ctcttcctcc tggagatctc cgcgtccggc tcgctccacg gtggcggcga 10320 ggtcgttgga aatgcgggcc atgagctgcg agaaggcgtt gaggcctccc tcgttccaga 10380 cgcggctgta gaccacgccc ccttcggcat cgcgggcgcg catgaccacc tgcgcgagat 10440 tgagctccac gtgccgggcg aagacggcgt agtttcgcag gcgctgaaag aggtagttga 10500 gggtggtggc ggtgtgttct gccacgaaga agtacataac ccagcgtcgc aacgtggatt 10560 cgttgatatc ccccaaggcc tcaaggcgct ccatggcctc gtagaagtcc acggcgaagt 10620 tgaaaaactg ggagttgcgc gccgacacgg ttaactcctc ctccagaaga cggatgagct 10680 cggcgacagt gtcgcgcacc tcgcgctcaa aggctacagg ggcctcttct tcttcttcaa 10740 tctcctcttc cataagggcc tccccttctt cttcttctgg cggcggtggg ggagggggga 10800 cacggcggcg acgacggcgc accgggaggc ggtcgacaaa gcgctcgatc atctccccgc 10860 ggcgacggcg catggtctcg gtgacggcgc ggccgttctc gcgggggcgc agttggaaga 10920 cgccgcccgt catgtcccgg ttatgggttg gcggggggct gccatgcggc agggatacgg 10980 cgctaacgat gcatctcaac aattgttgtg taggtactcc gccgccgagg gacctgagcg 11040 agtccgcatc gaccggatcg gaaaacctct cgagaaaggc gtctaaccag tcacagtcgc 11100 aaggtaggct gagcaccgtg gcgggcggca gcgggcggcg gtcggggttg tttctggcgg 11160 aggtgctgct gatgatgtaa ttaaagtagg cggtcttgag acggcggatg gtcgacagaa 11220 gcaccatgtc cttgggtccg gcctgctgaa tgcgcaggcg gtcggccatg ccccaggctt 11280 cgttttgaca tcggcgcagg tctttgtagt agtcttgcat gagcctttct accggcactt 11340 cttcttctcc ttcctcttgt cctgcatctc ttgcatctat cgctgcggcg gcggcggagt 11400 ttggccgtag gtggcgccct cttcctccca tgcgtgtgac cccgaagccc ctcatcggct 11460 gaagcagggc taggtcggcg acaacgcgct cggctaatat ggcctgctgc acctgcgtga 11520 gggtagactg gaagtcatcc atgtccacaa agcggtggta tgcgcccgtg ttgatggtgt 11580 aagtgcagtt ggccataacg gaccagttaa cggtctggtg acccggctgc gagagctcgg 11640 tgtacctgag acgcgagtaa gccctcgagt caaatacgta gtcgttgcaa gtccgcacca 11700 ggtactggta tcccaccaaa aagtgcggcg gcggctggcg gtagaggggc cagcgtaggg 11760 tggccggggc tccgggggcg agatcttcca acataaggcg atgatatccg tagatgtacc 11820 tggacatcca ggtgatgccg gcggcggtgg tggaggcgcg cggaaagtcg cggacgcggt 11880 tccagatgtt gcgcagcggc aaaaagtgct ccatggtcgg gacgctctgg ccggtcaggc 11940 gcgcgcaatc gttgacgctc tagcgtgcaa aaggagagcc tgtaagcggg cactcttccg 12000 tggtctggtg gataaattcg caagggtatc atggcggacg accggggttc gagccccgta 12060 tccggccgtc cgccgtgatc catgcggtta ccgcccgcgt gtcgaaccca ggtgtgcgac 12120 gtcagacaac gggggagtgc tccttttggc ttccttccag gcgcggcggc tgctgcgcta 12180 gcttttttgg ccactggccg cgcgcagcgt aagcggttag gctggaaagc gaaagcatta 12240 agtggctcgc tccctgtagc cggagggtta ttttccaagg gttgagtcgc gggacccccg 12300 gttcgagtct cggaccggcc ggactgcggc gaacgggggt ttgcctcccc gtcatgcaag 12360 accccgcttg caaattcctc cggaaacagg gacgagcccc ttttttgctt ttcccagatg 12420 catccggtgc tgcggcagat gcgcccccct cctcagcagc ggcaagagca agagcagcgg 12480 cagacatgca gggcaccctc ccctcctcct accgcgtcag gaggggcgac atccgcggtt 12540 gacgcggcag cagatggtga ttacgaaccc ccgcggcgcc gggcccggca ctacctggac 12600 ttggaggagg gcgagggcct ggcgcggcta ggagcgccct ctcctgagcg gcacccaagg 12660 gtgcagctga agcgtgatac gcgtgaggcg tacgtgccgc ggcagaacct gtttcgcgac 12720 cgcgagggag aggagcccga ggagatgcgg gatcgaaagt tccacgcagg gcgcgagctg 12780 cggcatggcc tgaatcgcga gcggttgctg cgcgaggagg actttgagcc cgacgcgcga 12840 accgggatta gtcccgcgcg cgcacacgtg gcggccgccg acctggtaac cgcatacgag 12900 cagacggtga accaggagat taactttcaa aaaagcttta acaaccacgt gcgtacgctt 12960 gtggcgcgcg aggaggtggc tataggactg atgcatctgt gggactttgt aagcgcgctg 13020 gagcaaaacc caaatagcaa gccgctcatg gcgcagctgt tccttatagt gcagcacagc 13080 agggacaacg aggcattcag ggatgcgctg ctaaacatag tagagcccga gggccgctgg 13140 ctgctcgatt tgataaacat cctgcagagc atagtggtgc aggagcgcag cttgagcctg 13200 gctgacaagg tggccgccat caactattcc atgcttagcc tgggcaagtt ttacgcccgc 13260 aagatatacc atacccctta cgttcccata gacaaggagg taaagatcga ggggttctac 13320 atgcgcatgg cgctgaaggt gcttaccttg agcgacgacc tgggcgttta tcgcaacgag 13380 cgcatccaca aggccgtgag cgtgagccgg cggcgcgagc tcagcgaccg cgagctgatg 13440 cacagcctgc aaagggccct ggctggcacg ggcagcggcg atagagaggc cgagtcctac 13500 tttgacgcgg gcgctgacct gcgctgggcc ccaagccgac gcgccctgga ggcagctggg 13560 gccggacctg ggctggcggt ggcacccgcg cgcgctggca acgtcggcgg cgtggaggaa 13620 tatgacgagg acgatgagta cgagccagag gacggcgagt actaagcggt gatgtttctg 13680 atcagatgat gcaagacgca acggacccgg cggtgcgggc ggcgctgcag agccagccgt 13740 ccggccttaa ctccacggac gactggcgcc aggtcatgga ccgcatcatg tcgctgactg 13800 cgcgcaatcc tgacgcgttc cggcagcagc cgcaggccaa ccggctctcc gcaattctgg 13860 aagcggtggt cccggcgcgc gcaaacccca cgcacgagaa ggtgctggcg atcgtaaacg 13920 cgctggccga aaacagggcc atccggcccg acgaggccgg cctggtctac gacgcgctgc 13980 ttcagcgcgt ggctcgttac aacagcggca acgtgcagac caacctggac cggctggtgg 14040 gggatgtgcg cgaggccgtg gcgcagcgtg agcgcgcgca gcagcagggc aacctgggct 14100 ccatggttgc actaaacgcc ttcctgagta cacagcccgc caacgtgccg cggggacagg 14160 aggactacac caactttgtg agcgcactgc ggctaatggt gactgagaca ccgcaaagtg 14220 aggtgtacca gtctgggcca gactattttt tccagaccag tagacaaggc ctgcagaccg 14280 taaacctgag ccaggctttc aaaaacttgc aggggctgtg gggggtgcgg gctcccacag 14340 gcgaccgcgc gaccgtgtct agcttgctga cgcccaactc gcgcctgttg ctgctgctaa 14400 tagcgccctt cacggacagt ggcagcgtgt cccgggacac atacctaggt cacttgctga 14460 cactgtaccg cgaggccata ggtcaggcgc atgtggacga gcatactttc caggagatta 14520 caagtgtcag ccgcgcgctg gggcaggagg acacgggcag cctggaggca accctaaact 14580 acctgctgac caaccggcgg cagaagatcc cctcgttgca cagtttaaac agcgaggagg 14640 agcgcatttt gcgctacgtg cagcagagcg tgagccttaa cctgatgcgc gacggggtaa 14700 cgcccagcgt ggcgctggac atgaccgcgc gcaacatgga accgggcatg tatgcctcaa 14760 accggccgtt tatcaaccgc ctaatggact acttgcatcg cgcggccgcc gtgaaccccg 14820 agtatttcac caatgccatc ttgaacccgc actggctacc gccccctggt ttctacaccg 14880 ggggattcga ggtgcccgag ggtaacgatg gattcctctg ggacgacata gacgacagcg 14940 tgttttcccc gcaaccgcag accctgctag agttgcaaca gcgcgagcag gcagaggcgg 15000 cgctgcgaaa ggaaagcttc cgcaggccaa gcagcttgtc cgatctaggc gctgcggccc 15060 cgcggtcaga tgctagtagc ccatttccaa gcttgatagg gtctcttacc agcactcgca 15120 ccacccgccc gcgcctgctg ggcgaggagg agtacctaaa caactcgctg ctgcagccgc 15180 agcgcgaaaa aaacctgcct ccggcatttc ccaacaacgg gatagagagc ctagtggaca 15240 agatgagtag atggaagacg tacgcgcagg agcacaggga cgtgccaggc ccgcgcccgc 15300 ccacccgtcg tcaaaggcac gaccgtcagc ggggtctggt gtgggaggac gatgactcgg 15360 cagacgacag cagcgtcctg gatttgggag ggagtggcaa cccgtttgcg caccttcgcc 15420 ccaggctggg gagaatgttt taaaaaaaaa aaagcatgat gcaaaataaa aaactcacca 15480 aggccatggc accgagcgtt ggttttcttg tattcccctt agtatgcggc gcgcggcgat 15540 gtatgaggaa ggtcctcctc cctcctacga gagtgtggtg agcgcggcgc cagtggcggc 15600 ggcgctgggt tctcccttcg atgctcccct ggacccgccg tttgtgcctc cgcggtacct 15660 gcggcctacc ggggggagaa acagcatccg ttactctgag ttggcacccc tattcgacac 15720 cacccgtgtg tacctggtgg acaacaagtc aacggatgtg gcatccctga actaccagaa 15780 cgaccacagc aactttctga ccacggtcat tcaaaacaat gactacagcc cgggggaggc 15840 aagcacacag accatcaatc ttgacgaccg gtcgcactgg ggcggcgacc tgaaaaccat 15900 cctgcatacc aacatgccaa atgtgaacga gttcatgttt accaataagt ttaaggcgcg 15960 ggtgatggtg tcgcgcttgc ctactaagga caatcaggtg gagctgaaat acgagtgggt 16020 ggagttcacg ctgcccgagg gcaactactc cgagaccatg accatagacc ttatgaacaa 16080 cgcgatcgtg gagcactact tgaaagtggg cagacagaac ggggttctgg aaagcgacat 16140 cggggtaaag tttgacaccc gcaacttcag actggggttt gaccccgtca ctggtcttgt 16200 catgcctggg gtatatacaa acgaagcctt ccatccagac atcattttgc tgccaggatg 16260 cggggtggac ttcacccaca gccgcctgag caacttgttg ggcatccgca agcggcaacc 16320 cttccaggag ggctttagga tcacctacga tgatctggag ggtggtaaca ttcccgcact 16380 gttggatgtg gacgcctacc aggcgagctt gaaagatgac accgaacagg gcgggggtgg 16440 cgcaggcggc agcaacagca gtggcagcgg cgcggaagag aactccaacg cggcagccgc 16500 ggcaatgcag ccggtggagg acatgaacga tcatgccatt cgcggcgaca cctttgccac 16560 acgggctgag gagaagcgcg ctgaggccga agcagcggcc gaagctgccg cccccgctgc 16620 gcaacccgag gtcgagaagc ctcagaagaa accggtgatc aaacccctga cagaggacag 16680 caagaaacgc agttacaacc taataagcaa tgacagcacc ttcacccagt accgcagctg 16740 gtaccttgca tacaactacg gcgaccctca gaccggaatc cgctcatgga ccctgctttg 16800 cactcctgac gtaacctgcg gctcggagca ggtctactgg tcgttgccag acatgatgca 16860 agaccccgtg accttccgct ccacgcgcca gatcagcaac tttccggtgg tgggcgccga 16920 gctgttgccc gtgcactcca agagcttcta caacgaccag gccgtctact cccaactcat 16980 ccgccagttt acctctctga cccacgtgtt caatcgcttt cccgagaacc agattttggc 17040 gcgcccgcca gcccccacca tcaccaccgt cagtgaaaac gttcctgctc tcacagatca 17100 cgggacgcta ccgctgcgca acagcatcgg aggagtccag cgagtgacca ttactgacgc 17160 cagacgccgc acctgcccct acgtttacaa ggccctgggc atagtctcgc cgcgcgtcct 17220 atcgagccgc actttttgag caagcatgtc catccttata tcgcccagca ataacacagg 17280 ctggggcctg cgcttcccaa gcaagatgtt tggcggggcc aagaagcgct ccgaccaaca 17340 cccagtgcgc gtgcgcgggc actaccgcgc gccctggggc gcgcacaaac gcggccgcac 17400 tgggcgcacc accgtcgatg acgccatcga cgcggtggtg gaggaggcgc gcaactacac 17460 gcccacgccg ccaccagtgt ccacagtgga cgcggccatt cagaccgtgg tgcgcggagc 17520 ccggcgctat gctaaaatga agagacggcg gaggcgcgta gcacgtcgcc accgccgccg 17580 acccggcact gccgcccaac gcgcggcggc ggccctgctt aaccgcgcac gtcgcaccgg 17640 ccgacgggcg gccatgcggg ccgctcgaag gctggccgcg ggtattgtca ctgtgccccc 17700 caggtccagg cgacgagcgg ccgccgcagc agccgcggcc attagtgcta tgactcaggg 17760 tcgcaggggc aacgtgtatt gggtgcgcga ctcggttagc ggcctgcgcg tgcccgtgcg 17820 cacccgcccc ccgcgcaact agattgcaag aaaaaactac ttagactcgt actgttgtat 17880 gtatccagcg gcggcggcgc gcaacgaagc tatgtccaag cgcaaaatca aagaagagat 17940 gctccaggtc atcgcgccgg agatctatgg ccccccgaag aaggaagagc aggattacaa 18000 gccccgaaag ctaaagcggg tcaaaaagaa aaagaaagat gatgatgatg aacttgacga 18060 cgaggtggaa ctgctgcacg ctaccgcgcc caggcgacgg gtacagtgga aaggtcgacg 18120 cgtaaaacgt gttttgcgac ccggcaccac cgtagtcttt acgcccggtg agcgctccac 18180 ccgcacctac aagcgcgtgt atgatgaggt gtacggcgac gaggacctgc ttgagcaggc 18240 caacgagcgc ctcggggagt ttgcctacgg aaagcggcat aaggacatgc tggcgttgcc 18300 gctggacgag ggcaacccaa cacctagcct aaagcccgta acactgcagc aggtgctgcc 18360 cgcgcttgca ccgtccgaag aaaagcgcgg cctaaagcgc gagtctggtg acttggcacc 18420 caccgtgcag ctgatggtac ccaagcgcca gcgactggaa gatgtcttgg aaaaaatgac 18480 cgtggaacct gggctggagc ccgaggtccg cgtgcggcca atcaagcagg tggcgccggg 18540 actgggcgtg cagaccgtgg acgttcagat acccactacc agtagcacca gtattgccac 18600 cgccacagag ggcatggaga cacaaacgtc cccggttgcc tcagcggtgg cggatgccgc 18660 ggtgcaggcg gtcgctgcgg ccgcgtccaa gacctctacg gaggtgcaaa cggacccgtg 18720 gatgtttcgc gtttcagccc cccggcgccc gcgccgttcg aggaagtacg gcgccgccag 18780 cgcgctactg cccgaatatg ccctacatcc ttccattgcg cctacccccg gctatcgtgg 18840 ctacacctac cgccccagaa gacgagcaac tacccgacgc cgaaccacca ctggaacccg 18900 ccgccgccgt cgccgtcgcc agcccgtgct ggccccgatt tccgtgcgca gggtggctcg 18960 cgaaggaggc aggaccctgg tgctgccaac agcgcgctac caccccagca tcgtttaaaa 19020 gccggtcttt gtggttcttg cagatatggc cctcacctgc cgcctccgtt tcccggtgcc 19080 gggattccga ggaagaatgc accgtaggag gggcatggcc ggccacggcc tgacgggcgg 19140 catgcgtcgt gcgcaccacc ggcggcggcg cgcgtcgcac cgtcgcatgc gcggcggtat 19200 cctgcccctc cttattccac tgatcgccgc ggcgattggc gccgtgcccg gaattgcatc 19260 cgtggccttg caggcgcaga gacactgatt aaaaacaagt tgcatgtgga aaaatcaaaa 19320 taaaaagtct ggactctcac gctcgcttgg tcctgtaact attttgtaga atggaagaca 19380 tcaactttgc gtctctggcc ccgcgacacg gctcgcgccc gttcatggga aactggcaag 19440 atatcggcac cagcaatatg agcggtggcg ccttcagctg gggctcgctg tggagcggca 19500 ttaaaaattt cggttccacc gttaagaact atggcagcaa ggcctggaac agcagcacag 19560 gccagatgct gagggataag ttgaaagagc aaaatttcca acaaaaggtg gtagatggcc 19620 tggcctctgg cattagcggg gtggtggacc tggccaacca ggcagtgcaa aataagatta 19680 acagtaagct tgatccccgc cctcccgtag aggagcctcc accggccgtg gagacagtgt 19740 ctccagaggg gcgtggcgaa aagcgtccgc gccccgacag ggaagaaact ctggtgacgc 19800 aaatagacga gcctccctcg tacgaggagg cactaaagca aggcctgccc accacccgtc 19860 ccatcgcgcc catggctacc ggagtgctgg gccagcacac acccgtaacg ctggacctgc 19920 ctccccccgc cgacacccag cagaaacctg tgctgccagg cccgaccgcc gttgttgtaa 19980 cccgtcctag ccgcgcgtcc ctgcgccgcg ccgccagcgg tccgcgatcg ttgcggcccg 20040 tagccagtgg caactggcaa agcacactga acagcatcgt gggtctgggg gtgcaatccc 20100 tgaagcgccg acgatgcttc tgatagctaa cgtgtcgtat gtgtgtcatg tatgcgtcca 20160 tgtcgccgcc agaggagctg ctgagccgcc gcgcgcccgc tttccaagat ggctacccct 20220 tcgatgatgc cgcagtggtc ttacatgcac atctcgggcc aggacgcctc ggagtacctg 20280 agccccgggc tggtgcagtt tgcccgcgcc accgagacgt acttcagcct gaataacaag 20340 tttagaaacc ccacggtggc gcctacgcac gacgtgacca cagaccggtc ccagcgtttg 20400 acgctgcggt tcatccctgt ggaccgtgag gatactgcgt actcgtacaa ggcgcggttc 20460 accctagctg tgggtgataa ccgtgtgctg gacatggctt ccacgtactt tgacatccgc 20520 ggcgtgctgg acaggggccc tacttttaag ccctactctg gcactgccta caacgccctg 20580 gctcccaagg gtgccccaaa tccttgcgaa tgggatgaag ctgctactgc tcttgaaata 20640 aacctagaag aagaggacga tgacaacgaa gacgaagtag acgagcaagc tgagcagcaa 20700 aaaactcacg tatttgggca ggcgccttat tctggtataa atattacaaa ggagggtatt 20760 caaataggtg tcgaaggtca aacacctaaa tatgccgata aaacatttca acctgaacct 20820 caaataggag aatctcagtg gtacgaaaca gaaattaatc atgcagctgg gagagtccta 20880 aaaaagacta ccccaatgaa accatgttac ggttcatatg caaaacccac aaatgaaaat 20940 ggagggcaag gcattcttgt aaagcaacaa aatggaaagc tagaaagtca agtggaaatg 21000 caatttttct caactactga ggcagccgca ggcaatggtg ataacttgac tcctaaagtg 21060 gtattgtaca gtgaagatgt agatatagaa accccagaca ctcatatttc ttacatgccc 21120 actattaagg aaggtaactc acgagaacta atgggccaac aatctatgcc caacaggcct 21180 aattacattg cttttaggga caattttatt ggtctaatgt attacaacag cacgggtaat 21240 atgggtgttc tggcgggcca agcatcgcag ttgaatgctg ttgtagattt gcaagacaga 21300 aacacagagc tttcatacca gcttttgctt gattccattg gtgatagaac caggtacttt 21360 tctatgtgga atcaggctgt tgacagctat gatccagatg ttagaattat tgaaaatcat 21420 ggaactgaag atgaacttcc aaattactgc tttccactgg gaggtgtgat taatacagag 21480 actcttacca aggtaaaacc taaaacaggt caggaaaatg gatgggaaaa agatgctaca 21540 gaattttcag ataaaaatga aataagagtt ggaaataatt ttgccatgga aatcaatcta 21600 aatgccaacc tgtggagaaa tttcctgtac tccaacatag cgctgtattt gcccgacaag 21660 ctaaagtaca gtccttccaa cgtaaaaatt tctgataacc caaacaccta cgactacatg 21720 aacaagcgag tggtggctcc cgggctagtg gactgctaca ttaaccttgg agcacgctgg 21780 tcccttgact atatggacaa cgtcaaccca tttaaccacc accgcaatgc tggcctgcgc 21840 taccgctcaa tgttgctggg caatggtcgc tatgtgccct tccacatcca ggtgcctcag 21900 aagttctttg ccattaaaaa cctccttctc ctgccgggct catacaccta cgagtggaac 21960 ttcaggaagg atgttaacat ggttctgcag agctccctag gaaatgacct aagggttgac 22020 ggagccagca ttaagtttga tagcatttgc ctttacgcca ccttcttccc catggcccac 22080 aacaccgcct ccacgcttga ggccatgctt agaaacgaca ccaacgacca gtcctttaac 22140 gactatctct ccgccgccaa catgctctac cctatacccg ccaacgctac caacgtgccc 22200 atatccatcc cctcccgcaa ctgggcggct ttccgcggct gggccttcac gcgccttaag 22260 actaaggaaa ccccatcact gggctcgggc tacgaccctt attacaccta ctctggctct 22320 ataccctacc tagatggaac cttttacctc aaccacacct ttaagaaggt ggccattacc 22380 tttgactctt ctgtcagctg gcctggcaat gaccgcctgc ttacccccaa cgagtttgaa 22440 attaagcgct cagttgacgg ggagggttac aacgttgccc agtgtaacat gaccaaagac 22500 tggttcctgg tacaaatgct agctaactat aacattggct accagggctt ctatatccca 22560 gagagctaca aggaccgcat gtactccttc tttagaaact tccagcccat gagccgtcag 22620 gtggtggatg atactaaata caaggactac caacaggtgg gcatcctaca ccaacacaac 22680 aactctggat ttgttggcta ccttgccccc accatgcgcg aaggacaggc ctaccctgct 22740 aacttcccct atccgcttat aggcaagacc gcagttgaca gcattaccca gaaaaagttt 22800 ctttgcgatc gcaccctttg gcgcatccca ttctccagta actttatgtc catgggcgca 22860 ctcacagacc tgggccaaaa ccttctctac gccaactccg cccacgcgct agacatgact 22920 tttgaggtgg atcccatgga cgagcccacc cttctttatg ttttgtttga agtctttgac 22980 gtggtccgtg tgcaccagcc gcaccgcggc gtcatcgaaa ccgtgtacct gcgcacgccc 23040 ttctcggccg gcaacgccac aacataaaga agcaagcaac atcaacaaca gctgccgcca 23100 tgggctccag tgagcaggaa ctgaaagcca ttgtcaaaga tcttggttgt gggccatatt 23160 ttttgggcac ctatgacaag cgctttccag gctttgtttc tccacacaag ctcgcctgcg 23220 ccatagtcaa tacggccggt cgcgagactg ggggcgtaca ctggatggcc tttgcctgga 23280 acccgcactc aaaaacatgc tacctctttg agccctttgg cttttctgac cagcgactca 23340 agcaggttta ccagtttgag tacgagtcac tcctgcgccg tagcgccatt gcttcttccc 23400 ccgaccgctg tataacgctg gaaaagtcca cccaaagcgt acaggggccc aactcggccg 23460 cctgtggact attctgctgc atgtttctcc acgcctttgc caactggccc caaactccca 23520 tggatcacaa ccccaccatg aaccttatta ccggggtacc caactccatg ctcaacagtc 23580 cccaggtaca gcccaccctg cgtcgcaacc aggaacagct ctacagcttc ctggagcgcc 23640 actcgcccta cttccgcagc cacagtgcgc agattaggag cgccacttct ttttgtcact 23700 tgaaaaacat gtaaaaataa tgtactagag acactttcaa taaaggcaaa tgcttttatt 23760 tgtacactct cgggtgatta tttaccccca cccttgccgt ctgcgccgtt taaaaatcaa 23820 aggggttctg ccgcgcatcg ctatgcgcca ctggcaggga cacgttgcga tactggtgtt 23880 tagtgctcca cttaaactca ggcacaacca tccgcggcag ctcggtgaag ttttcactcc 23940 acaggctgcg caccatcacc aacgcgttta gcaggtcggg cgccgatatc ttgaagtcgc 24000 agttggggcc tccgccctgc gcgcgcgagt tgcgatacac agggttgcag cactggaaca 24060 ctatcagcgc cgggtggtgc acgctggcca gcacgctctt gtcggagatc agatccgcgt 24120 ccaggtcctc cgcgttgctc agggcgaacg gagtcaactt tggtagctgc cttcccaaaa 24180 agggcgcgtg cccaggcttt gagttgcact cgcaccgtag tggcatcaaa aggtgaccgt 24240 gcccggtctg ggcgttagga tacagcgcct gcataaaagc cttgatctgc ttaaaagcca 24300 cctgagcctt tgcgccttca gagaagaaca tgccgcaaga cttgccggaa aactgattgg 24360 ccggacaggc cgcgtcgtgc acgcagcacc ttgcgtcggt gttggagatc tgcaccacat 24420 ttcggcccca ccggttcttc acgatcttgg ccttgctaga ctgctccttc agcgcgcgct 24480 gcccgttttc gctcgtcaca tccatttcaa tcacgtgctc cttatttatc ataatgcttc 24540 cgtgtagaca cttaagctcg ccttcgatct cagcgcagcg gtgcagccac aacgcgcagc 24600 ccgtgggctc gtgatgcttg taggtcacct ctgcaaacga ctgcaggtac gcctgcagga 24660 atcgccccat catcgtcaca aaggtcttgt tgctggtgaa ggtcagctgc aacccgcggt 24720 gctcctcgtt cagccaggtc ttgcatacgg ccgccagagc ttccacttgg tcaggcagta 24780 gtttgaagtt cgcctttaga tcgttatcca cgtggtactt gtccatcagc gcgcgcgcag 24840 cctccatgcc cttctcccac gcagacacga tcggcacact cagcgggttc atcaccgtaa 24900 tttcactttc cgcttcgctg ggctcttcct cttcctcttg cgtccgcata ccacgcgcca 24960 ctgggtcgtc ttcattcagc cgccgcactg tgcgcttacc tcctttgcca tgcttgatta 25020 gcaccggtgg gttgctgaaa cccaccattt gtagcgccac atcttctctt tcttcctcgc 25080 tgtccacgat tacctctggt gatggcgggc gctcgggctt gggagaaggg cgcttctttt 25140 tcttcttggg cgcaatggcc aaatccgccg ccgaggtcga tggccgcggg ctgggtgtgc 25200 gcggcaccag cgcgtcttgt gatgagtctt cctcgtcctc ggactcgata cgccgcctca 25260 tccgcttttt tgggggcgcc cggggaggcg gcggcgacgg ggacggggac gacacgtcct 25320 ccatggttgg gggacgtcgc gccgcaccgc gtccgcgctc gggggtggtt tcgcgctgct 25380 cctcttcccg actggccatt tccttctcct ataggcagaa aaagatcatg gagtcagtcg 25440 agaagaagga cagcctaacc gccccctctg agttcgccac caccgcctcc accgatgccg 25500 ccaacgcgcc taccaccttc cccgtcgagg cacccccgct tgaggaggag gaagtgatta 25560 tcgagcagga cccaggtttt gtaagcgaag acgacgagga ccgctcagta ccaacagagg 25620 ataaaaagca agaccaggac aacgcagagg caaacgagga acaagtcggg cggggggacg 25680 aaaggcatgg cgactaccta gatgtgggag acgacgtgct gttgaagcat ctgcagcgcc 25740 agtgcgccat tatctgcgac gcgttgcaag agcgcagcga tgtgcccctc gccatagcgg 25800 atgtcagcct tgcctacgaa cgccacctat tctcaccgcg cgtacccccc aaacgccaag 25860 aaaacggcac atgcgagccc aacccgcgcc tcaacttcta ccccgtattt gccgtgccag 25920 aggtgcttgc cacctatcac atctttttcc aaaactgcaa gataccccta tcctgccgtg 25980 ccaaccgcag ccgagcggac aagcagctgg ccttgcggca gggcgctgtc atacctgata 26040 tcgcctcgct caacgaagtg ccaaaaatct ttgagggtct tggacgcgac gagaagcgcg 26100 cggcaaacgc tctgcaacag gaaaacagcg aaaatgaaag tcactctgga gtgttggtgg 26160 aactcgaggg tgacaacgcg cgcctagccg tactaaaacg cagcatcgag gtcacccact 26220 ttgcctaccc ggcacttaac ctacccccca aggtcatgag cacagtcatg agtgagctga 26280 tcgtgcgccg tgcgcagccc ctggagaggg atgcaaattt gcaagaacaa acagaggagg 26340 gcctacccgc agttggcgac gagcagctag cgcgctggct tcaaacgcgc gagcctgccg 26400 acttggagga gcgacgcaaa ctaatgatgg ccgcagtgct cgttaccgtg gagcttgagt 26460 gcatgcagcg gttctttgct gacccggaga tgcagcgcaa gctagaggaa acattgcact 26520 acacctttcg acagggctac gtacgccagg cctgcaagat ctccaacgtg gagctctgca 26580 acctggtctc ctaccttgga attttgcacg aaaaccgcct tgggcaaaac gtgcttcatt 26640 ccacgctcaa gggcgaggcg cgccgcgact acgtccgcga ctgcgtttac ttatttctat 26700 gctacacctg gcagacggcc atgggcgttt ggcagcagtg cttggaggag tgcaacctca 26760 aggagctgca gaaactgcta aagcaaaact tgaaggacct atggacggcc ttcaacgagc 26820 gctccgtggc cgcgcacctg gcggacatca ttttccccga acgcctgctt aaaaccctgc 26880 aacagggtct gccagacttc accagtcaaa gcatgttgca gaactttagg aactttatcc 26940 tagagcgctc aggaatcttg cccgccacct gctgtgcact tcctagcgac tttgtgccca 27000 ttaagtaccg cgaatgccct ccgccgcttt ggggccactg ctaccttctg cagctagcca 27060 actaccttgc ctaccactct gacataatgg aagacgtgag cggtgacggt ctactggagt 27120 gtcactgtcg ctgcaaccta tgcaccccgc accgctccct ggtttgcaat tcgcagctgc 27180 ttaacgaaag tcaaattatc ggtacctttg agctgcaggg tccctcgcct gacgaaaagt 27240 ccgcggctcc ggggttgaaa ctcactccgg ggctgtggac gtcggcttac cttcgcaaat 27300 ttgtacctga ggactaccac gcccacgaga ttaggttcta cgaagaccaa tcccgcccgc 27360 ctaatgcgga gcttaccgcc tgcgtcatta cccagggcca cattcttggc caattgcaag 27420 ccatcaacaa agcccgccaa gagtttctgc tacgaaaggg acggggggtt tacttggacc 27480 cccagtccgg cgaggagctc aacccaatcc ccccgccgcc gcagccctat cagcagcagc 27540 cgcgggccct tgcttcccag gatggcaccc aaaaagaagc tgcagctgcc gccgccaccc 27600 acggacgagg aggaatactg ggacagtcag gcagaggagg ttttggacga ggaggaggag 27660 gacatgatgg aagactggga gagcctagac gaggaagctt ccgaggtcga agaggtgtca 27720 gacgaaacac cgtcaccctc ggtcgcattc ccctcgccgg cgccccagaa atcggcaacc 27780 ggttccagca tggctacaac ctccgctcct caggcgccgc cggcactgcc cgttcgccga 27840 cccaaccgta gatgggacac cactggaacc agggccggta agtccaagca gccgccgccg 27900 ttagcccaag agcaacaaca gcgccaaggc taccgctcat ggcgcgggca caagaacgcc 27960 atagttgctt gcttgcaaga ctgtgggggc aacatctcct tcgcccgccg ctttcttctc 28020 taccatcacg gcgtggcctt cccccgtaac atcctgcatt actaccgtca tctctacagc 28080 ccatactgca ccggcggcag cggcagcaac agcagcggcc acacagaagc aaaggcgacc 28140 ggatagcaag actctgacaa agcccaagaa atccacagcg gcggcagcag caggaggagg 28200 agcgctgcgt ctggcgccca acgaacccgt atcgacccgc gagcttagaa acaggatttt 28260 tcccactctg tatgctatat ttcaacagag caggggccaa gaacaagagc tgaaaataaa 28320 aaacaggtct ctgcgatccc tcacccgcag ctgcctgtat cacaaaagcg aagatcagct 28380 tcggcgcacg ctggaagacg cggaggctct cttcagtaaa tactgcgcgc tgactcttaa 28440 ggactagttt cgcgcccttt ctcaaattta agcgcgaaaa ctacgtcatc tccagcggcc 28500 acacccggcg ccagcacctg ttgtcagcgc cattatgagc aaggaaattc ccacgcccta 28560 catgtggagt taccagccac aaatgggact tgcggctgga gctgcccaag actactcaac 28620 ccgaataaac tacatgagcg cgggacccca catgatatcc cgggtcaacg gaatacgcgc 28680 ccaccgaaac cgaattctcc tggaacaggc ggctattacc accacacctc gtaataacct 28740 taatccccgt agttggcccg ctgccctggt gtaccaggaa agtcccgctc ccaccactgt 28800 ggtacttccc agagacgccc aggccgaagt tcagatgact aactcagggg cgcagcttgc 28860 gggcggcttt cgtcacaggg tgcggtcgcc cgggcagggt ataactcacc tgacaatcag 28920 agggcgaggt attcagctca acgacgagtc ggtgagctcc tcgcttggtc tccgtccgga 28980 cgggacattt cagatcggcg gcgccggccg ctcttcattc acgcctcgtc aggcaatcct 29040 aactctgcag acctcgtcct ctgagccgcg ctctggaggc attggaactc tgcaatttat 29100 tgaggagttt gtgccatcgg tctactttaa ccccttctcg ggacctcccg gccactatcc 29160 ggatcaattt attcctaact ttgacgcggt aaaggactcg gcggacggct acgactgaat 29220 gttaagtgga gaggcagagc aactgcgcct gaaacacctg gtccactgtc gccgccacaa 29280 gtgctttgcc cgcgactccg gtgagttttg ctactttgaa ttgcccgagg atcatatcga 29340 gggcccggcg cacggcgtcc ggcttaccgc ccagggagag cttgcccgta gcctgattcg 29400 ggagtttacc cagcgccccc tgctagttga gcgggacagg ggaccctgtg ttctcactgt 29460 gatttgcaac tgtcctaacc ctggattaca tcaagatcct ctagttaatg tcaggtcgcc 29520 taagtcgatt aactagagta cccggggatc ttattccctt taactaataa aaaaaaataa 29580 taaagcatca cttacttaaa atcagttagc aaatttctgt ccagtttatt cagcagcacc 29640 tccttgccct cctcccagct ctggtattgc agcttcctcc tggctgcaaa ctttctccac 29700 aatctaaatg gaatgtcagt ttcctcctgt tcctgtccat ccgcacccac tatcttcatg 29760 ttgttgcaga tgaagcgcgc aagaccgtct gaagatacct tcaaccccgt gtatccatat 29820 gacacggaaa ccggtcctcc aactgtgcct tttcttactc ctccctttgt atcccccaat 29880 gggtttcaag agagtccccc tggggtactc tctttgcgcc tatccgaacc tctagttacc 29940 tccaatggca tgcttgcgct caaaatgggc aacggcctct ctctggacga ggccggcaac 30000 cttacctccc aaaatgtaac cactgtgagc ccacctctca aaaaaaccaa gtcaaacata 30060 aacctggaaa tatctgcacc cctcacagtt acctcagaag ccctaactgt ggctgccgcc 30120 gcacctctaa tggtcgcggg caacacactc accatgcaat cacaggcccc gctaaccgtg 30180 cacgactcca aacttagcat tgccacccaa ggacccctca cagtgtcaga aggaaagcta 30240 gccctgcaaa catcaggccc cctcaccacc accgatagca gtacccttac tatcactgcc 30300 tcaccccctc taactactgc cactggtagc ttgggcattg acttgaaaga gcccatttat 30360 acacaaaatg gaaaactagg actaaagtac ggggctcctt tgcatgtaac agacgaccta 30420 aacactttga ccgtagcaac tggtccaggt gtgactatta ataatacttc cttgcaaact 30480 aaagttactg gagccttggg ttttgattca caaggcaata tgcaacttaa tgtagcagga 30540 ggactaagga ttgattctca aaacagacgc cttatacttg atgttagtta tccgtttgat 30600 gctcaaaacc aactaaatct aagactagga cagggccctc tttttataaa ctcagcccac 30660 aacttggata ttaactacaa caaaggcctt tacttgttta cagcttcaaa caattccaaa 30720 aagcttgagg ttaacctaag cactgccaag gggttgatgt ttgacgctac agccatagcc 30780 attaatgcag gagatgggct tgaatttggt tcacctaatg caccaaacac aaatcccctc 30840 aaaacaaaaa ttggccatgg cctagaattt gattcaaaca aggctatggt tcctaaacta 30900 ggaactggcc ttagttttga cagcacaggt gccattacag taggaaacaa aaataatgat 30960 aagctaactt tgtggaccac accagctcca tctcctaact gtagactaaa tgcagagaaa 31020 gatgctaaac tcactttggt cttaacaaaa tgtggcagtc aaatacttgc tacagtttca 31080 gttttggctg ttaaaggcag tttggctcca atatctggaa cagttcaaag tgctcatctt 31140 attataagat ttgacgaaaa tggagtgcta ctaaacaatt ccttcctgga cccagaatat 31200 tggaacttta gaaatggaga tcttactgaa ggcacagcct atacaaacgc tgttggattt 31260 atgcctaacc tatcagctta tccaaaatct cacggtaaaa ctgccaaaag taacattgtc 31320 agtcaagttt acttaaacgg agacaaaact aaacctgtaa cactaaccat tacactaaac 31380 ggtacacagg aaacaggaga cacaactcca agtgcatact ctatgtcatt ttcatgggac 31440 tggtctggcc acaactacat taatgaaata tttgccacat cctcttacac tttttcatac 31500 attgcccaag aataaagaat cgtttgtgtt atgtttcaac gtgtttattt ttcaattgca 31560 gaaaatttca agtcattttt cattcagtag tatagcccca ccaccacata gcttatacag 31620 atcaccgtac cttaatcaaa ctcacagaac cctagtattc aacctgccac ctccctccca 31680 acacacagag tacacagtcc tttctccccg gctggcctta aaaagcatca tatcatgggt 31740 aacagacata ttcttaggtg ttatattcca cacggtttcc tgtcgagcca aacgctcatc 31800 agtgatatta ataaactccc cgggcagctc acttaagttc atgtcgctgt ccagctgctg 31860 agccacaggc tgctgtccaa cttgcggttg cttaacgggc ggcgaaggag aagtccacgc 31920 ctacatgggg gtagagtcat aatcgtgcat caggataggg cggtggtgct gcagcagcgc 31980 gcgaataaac tgctgccgcc gccgctccgt cctgcaggaa tacaacatgg cagtggtctc 32040 ctcagcgatg attcgcaccg cccgcagcat aaggcgcctt gtcctccggg cacagcagcg 32100 caccctgatc tcacttaaat cagcacagta actgcagcac agcaccacaa tattgttcaa 32160 aatcccacag tgcaaggcgc tgtatccaaa gctcatggcg gggaccacag aacccacgtg 32220 gccatcatac cacaagcgca ggtagattaa gtggcgaccc ctcataaaca cgctggacat 32280 aaacattacc tcttttggca tgttgtaatt caccacctcc cggtaccata taaacctctg 32340 attaaacatg gcgccatcca ccaccatcct aaaccagctg gccaaaacct gcccgccggc 32400 tatacactgc agggaaccgg gactggaaca atgacagtgg agagcccagg actcgtaacc 32460 atggatcatc atgctcgtca tgatatcaat gttggcacaa cacaggcaca cgtgcataca 32520 cttcctcagg attacaagct cctcccgcgt tagaaccata tcccagggaa caacccattc 32580 ctgaatcagc gtaaatccca cactgcaggg aagacctcgc acgtaactca cgttgtgcat 32640 tgtcaaagtg ttacattcgg gcagcagcgg atgatcctcc agtatggtag cgcgggtttc 32700 tgtctcaaaa ggaggtagac gatccctact gtacggagtg cgccgagaca accgagatcg 32760 tgttggtcgt agtgtcatgc caaatggaac gccggacgta gtcatatttc ctgaagcaaa 32820 accaggtgcg ggcgtgacaa acagatctgc gtctccggtc tcgccgctta gatcgctctg 32880 tgtagtagtt gtagtatatc cactctctca aagcatccag gcgccccctg gcttcgggtt 32940 ctatgtaaac tccttcatgc gccgctgccc tgataacatc caccaccgca gaataagcca 33000 cacccagcca acctacacat tcgttctgcg agtcacacac gggaggagcg ggaagagctg 33060 gaagaaccat gttttttttt ttattccaaa agattatcca aaacctcaaa atgaagatct 33120 attaagtgaa cgcgctcccc tccggtggcg tggtcaaact ctacagccaa agaacagata 33180 atggcatttg taagatgttg cacaatggct tccaaaaggc aaacggccct cacgtccaag 33240 tggacgtaaa ggctaaaccc ttcagggtga atctcctcta taaacattcc agcaccttca 33300 accatgccca aataattctc atctcgccac cttctcaata tatctctaag caaatcccga 33360 atattaagtc cggccattgt aaaaatctgc tccagagcgc cctccacctt cagcctcaag 33420 cagcgaatca tgattgcaaa aattcaggtt cctcacagac ctgtataaga ttcaaaagcg 33480 gaacattaac aaaaataccg cgatcccgta ggtcccttcg cagggccagc tgaacataat 33540 cgtgcaggtc tgcacggacc agcgcggcca cttccccgcc aggaaccatg acaaaagaac 33600 ccacactgat tatgacacgc atactcggag ctatgctaac cagcgtagcc ccgatgtaag 33660 cttgttgcat gggcggcgat ataaaatgca aggtgctgct caaaaaatca ggcaaagcct 33720 cgcgcaaaaa agaaagcaca tcgtagtcat gctcatgcag ataaaggcag gtaagctccg 33780 gaaccaccac agaaaaagac accatttttc tctcaaacat gtctgcgggt ttctgcataa 33840 acacaaaata aaataacaaa aaaacattta aacattagaa gcctgtctta caacaggaaa 33900 aacaaccctt ataagcataa gacggactac ggccatgccg gcgtgaccgt aaaaaaactg 33960 gtcaccgtga ttaaaaagca ccaccgacag ctcctcggtc atgtccggag tcataatgta 34020 agactcggta aacacatcag gttgattcac atcggtcagt gctaaaaagc gaccgaaata 34080 gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca taggaggtat 34140 aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct gcctaggcaa 34200 aatagcaccc tcccgctcca gaacaacata cagcgcttcc acagcggcag ccataacagt 34260 cagccttacc agtaaaaaag aaaacctatt aaaaaaacac cactcgacac ggcaccagct 34320 caatcagtca cagtgtaaaa aagggccaag tgcagagcga gtatatatag gactaaaaaa 34380 tgacgtaacg gttaaagtcc acaaaaaaca cccagaaaac cgcacgcgaa cctacgccca 34440 gaaacgaaag ccaaaaaacc cacaacttcc tcaaatcgtc acttccgttt tcccacgtta 34500 cgtcacttcc cattttaaga aaactacaat tcccaacaca tacaagttac tccgccctaa 34560 aacctacgtc acccgccccg ttcccacgcc ccgcgccacg tcacaaactc caccccctca 34620 ttatcatatt ggcttcaatc caaaataagg tatattattg atgat 34665 <210> SEQ ID NO 96 <211> LENGTH: 1644 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96 gtcgacgcca ccatgtgtca ccagcagctc gtgattagct ggttcagcct ggtgtttctg 60 gctagccctc tggtggccat ctgggagctg aagaaggacg tgtacgtggt ggagctcgac 120 tggtaccctg acgctcccgg cgagatggtc gtgctgacct gcgacacccc tgaggaagat 180 ggcatcacct ggaccctgga tcaaagctcc gaagtgctcg gcagcggcaa gacactcacc 240 atccaggtga aagagttcgg agacgccggc cagtacacct gccacaaagg cggcgaggtg 300 ctgtcccatt ccctgctgct gctgcacaag aaagaggatg gcatctggtc caccgacatc 360 ctgaaggacc agaaggaacc caagaacaag acctttctga gatgtgaggc caagaactac 420 agcggcaggt tcacctgctg gtggctgaca acaatctcca ccgacctgac cttcagcgtc 480 aagagcagca ggggcagcag cgaccctcaa ggcgtgacat gtggagccgc taccctgagc 540 gctgagagag tcaggggcga caataaggag tacgagtact ccgtggaatg ccaggaggac 600 tccgcctgcc ctgccgccga agagtccctc cctatcgaag tgatggttga tgccgtgcac 660 aagctcaagt atgagaatta caccagcagc tttttcatca gggacatcat caagcccgac 720 ccccccaaaa acctccagct gaaacccctc aagaatagca ggcaggtgga ggtctcctgg 780 gagtatcctg acacctggag caccccccac agctacttct ccctgacctt ctgtgtgcag 840 gtgcagggca agagcaaaag ggagaagaag gatagggtct ttaccgacaa gaccagcgcc 900 acagtgatct gcaggaagaa cgccagcatt tccgtcaggg cccaggacag gtactacagc 960 agcagctggt ccgagtgggc tagcgtgcct tgttccggcg gcggaggatc tggcggaggc 1020 ggaagtggcg gagggggctc tagaaacctc cccgtggcca cacccgaccc tggcatgttc 1080 ccctgcctcc accacagcca gaacctgctg agagccgtga gcaatatgct gcagaaggcc 1140 aggcaaaccc tggagttcta cccctgtacc tccgaggaga ttgaccatga ggacatcaca 1200 aaggacaaaa ccagcaccgt ggaggcctgt ctccccctcg aactgaccaa gaacgagtcc 1260 tgcctgaact ccagggagac atccttcatc accaacggct cctgcctggc ctccagaaag 1320 accagcttca tgatggccct ctgcctgagc agcatctacg aggacctcaa gatgtaccag 1380 gtggagttta aaacaatgaa cgccaagctc ctcatggacc ctaagaggca gattttcctc 1440 gaccagaata tgctggctgt cattgacgag ctgatgcagg ccctcaattt caactccgag 1500 accgtccccc agaagtcctc cctggaagag cccgactttt acaagaccaa gatcaagctc 1560 tgcatcctgc tgcacgcctt cagaattaga gccgtgacca ttgacagggt gatgagctac 1620 ctcaacgcct cctgatgact cgag 1644 <210> SEQ ID NO 97 <211> LENGTH: 2101 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 97 gtcgacgcca ccacatccgc ggcaacgcct ccttggtgtc gtccgcttcc aataacccag 60 cttgcgtcct gcacacttgt ggcttccgtg cacacattaa caactcatgg ttctagctcc 120 cagtcgccaa gcgttgccaa ggcgttgaga gatcatctgg gaagtctttt acccagaatt 180 gctttgattc aggccagctg gtttttcctg cggtgattcg gaaattcgcg aattcctctg 240 gtcctcatcc aggtgcgcgg gaagcaggtg cccaggagag aggggataat gaagattcca 300 tgctgatgat cccaaagatt gaacctgcag accaagcgca aagtagaaac tgaaagtaca 360 ctgctggcgg atcctacgga agttatggaa aaggcaaagc gcagagccac gccgtagtgt 420 gtgccgcccc ccttgggatg gatgaaactg cagtcgcggc gtgggtaaga ggaaccagct 480 gcagagatca ccctgcccaa cacagactcg gcaactccgc ggaagaccag ggtcctggga 540 gtgactatgg gcggtgagag cttgctcctg ctccagttgc ggtcatcatg actacgcccg 600 cctcccgcag accatgttcc atgtttcttt taggtatatc tttggacttc ctcccctgat 660 ccttgttctg ttgccagtag catcatctga ttgtgatatt gaaggtaaag atggcaaaca 720 atatgagagt gttctaatgg tcagcatcga tcaattattg gacagcatga aagaaattgg 780 tagcaattgc ctgaataatg aatttaactt ttttaaaaga catatctgtg atgctaataa 840 ggaaggtatg tttttattcc gtgctgctcg caagttgagg caatttctta aaatgaatag 900 cactggtgat tttgatctcc acttattaaa agtttcagaa ggcacaacaa tactgttgaa 960 ctgcactggc caggttaaag gaagaaaacc agctgccctg ggtgaagccc aaccaacaaa 1020 gagtttggaa gaaaataaat ctttaaagga acagaaaaaa ctgaatgact tgtgtttcct 1080 aaagagacta ttacaagaga taaaaacttg ttggaataaa attttgatgg gcactaaaga 1140 acactgaaaa atatggagtg gcaatataga aacacgaact ttagctgcat cctccaagaa 1200 tctatctgct tatgcagttt ttcagagtgg aatgcttcct agaagttact gaatgcacca 1260 tggtcaaaac ggattagggc atttgagaaa tgcatattgt attactagaa gatgaataca 1320 aacaatggaa actgaatgct ccagtcaaca aactatttct tatatatgtg aacatttatc 1380 aatcagtata attctgtact gatttttgta agacaatcca tgtaaggtat cagttgcaat 1440 aatacttctc aaacctgttt aaatatttca agacattaaa tctatgaagt atataatggt 1500 ttcaaagatt caaaattgac attgctttac tgtcaaaata attttatggc tcactatgaa 1560 tctattatac tgtattaaga gtgaaaattg tcttcttctg tgctggagat gttttagagt 1620 taacaatgat atatggataa tgccggtgag aataagagag tcataaacct taagtaagca 1680 acagcataac aaggtccaag atacctaaaa gagatttcaa gagatttaat taatcatgaa 1740 tgtgtaacac agtgccttca ataaatggta tagcaaatgt tttgacatga aaaaaggaca 1800 atttcaaaaa aataaaataa aataaaaata aattcaccta gtctaaggat gctaaacctt 1860 agtactgagt tacattgtca tttatataga ttataacttg tctaaataag tttgcaattt 1920 gggagatata tttttaagat aataatatat gtttaccttt taattaatga aatatctgta 1980 tttaattttg acactatatc tgtatataaa atattttcat acagcattac aaattgctta 2040 ctttggaata catttctcct ttgataaaat aaatgagcta tgtattaaaa aaaaaaaaaa 2100 a 2101 <210> SEQ ID NO 98 <211> LENGTH: 925 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 98 gtcgacgcca ccccagagag gggcaggctg gtcccctgac aggttgaagc aagtagacgc 60 ccaggagccc cgggaggggg ctgcagtttc cttccttcct tctcggcagc gctccgcgcc 120 cccatcgccc ctcctgcgct agcggaggtg atcgccgcgg cgatgccgga ggagggttcg 180 ggctgctcgg tgcggcgcag gccctatggg tgcgtcctgc gggctgcttt ggtcccattg 240 gtcgcgggct tggtgatctg cctcgtggtg tgcatccagc gcttcgcaca ggctcagcag 300 cagctgccgc tcgagtcact tgggtgggac gtagctgagc tgcagctgaa tcacacagga 360 cctcagcagg accccaggct atactggcag gggggcccag cactgggccg ctccttcctg 420 catggaccag agctggacaa ggggcagcta cgtatccatc gtgatggcat ctacatggta 480 cacatccagg tgacgctggc catctgctcc tccacgacgg cctccaggca ccaccccacc 540 accctggccg tgggaatctg ctctcccgcc tcccgtagca tcagcctgct gcgtctcagc 600 ttccaccaag gttgtaccat tgcctcccag cgcctgacgc ccctggcccg aggggacaca 660 ctctgcacca acctcactgg gacacttttg ccttcccgaa acactgatga gaccttcttt 720 ggagtgcagt gggtgcgccc ctgaccactg ctgctgatta gggtttttta aattttattt 780 tattttattt aagttcaaga gaaaaagtgt acacacaggg gccacccggg gttggggtgg 840 gagtgtggtg gggggtagtg gtggcaggac aagagaaggc attgagcttt ttctttcatt 900 ttcctattaa aaaatacaaa aatca 925 <210> SEQ ID NO 99 <211> LENGTH: 141 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 99 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcgcaag 60 tctatgttgt agtaaatttg ggcgtaaccg agtaagattt ggccattttc gcgggaaaac 120 tgaataagag gaagtgaaat c 141 <210> SEQ ID NO 100 <211> LENGTH: 142 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 100 acaggaagtg acatgttgca agtgtggcgg aacacatgta agcgacggat gtggcgcaag 60 tctatgttgt agtaaatttg ggcgtaaccg agtaagattt ggccattttc gcgggaaaac 120 tgaataagag gaagtgaaat ct 142 <210> SEQ ID NO 101 <211> LENGTH: 129 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 101 acaggaagtg acaattttcg cgcggtttta ggcggatgtg gcgcaagtct atgttgtagt 60 aaatttgggc gtaaccgagt aagatttggc cattttcgcg ggaaaactga ataagaggaa 120 gtgaaatct 129 <210> SEQ ID NO 102 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 102 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacggc ggaagtgtga attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataagagg aagtgaaatc t 201 <210> SEQ ID NO 103 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 103 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacggc ggaagtgtga attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataagagg atgtgaaatc t 201 <210> SEQ ID NO 104 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 104 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacggc ggaagtgtga attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataggcgg aagtgtgatc t 201 <210> SEQ ID NO 105 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 105 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacaca ggaagtgaca attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataggcgg aagtgtgatc t 201 <210> SEQ ID NO 106 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His <210> SEQ ID NO 107 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 107 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro 65 70 75 80 Leu Pro Ser Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn 85 90 95 Lys Val Ser Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu 100 105 110 Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro 115 120 125 Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr 130 135 140 Asn Lys Ser Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val 145 150 155 160 Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys 165 170 175 Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile 180 185 190 Ser

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 107 <210> SEQ ID NO 1 <211> LENGTH: 199 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 Met Thr Leu His Pro Ser Pro Ile Thr Cys Glu Phe Leu Phe Ser Thr 1 5 10 15 Ala Leu Ile Ser Pro Lys Met Cys Leu Ser His Leu Glu Asn Met Pro 20 25 30 Leu Ser His Ser Arg Thr Gln Gly Ala Gln Arg Ser Ser Trp Lys Leu 35 40 45 Trp Leu Phe Cys Ser Ile Val Met Leu Leu Phe Leu Cys Ser Phe Ser 50 55 60 Trp Leu Ile Phe Ile Phe Leu Gln Leu Glu Thr Ala Lys Glu Pro Cys 65 70 75 80 Met Ala Lys Phe Gly Pro Leu Pro Ser Lys Trp Gln Met Ala Ser Ser 85 90 95 Glu Pro Pro Cys Val Asn Lys Val Ser Asp Trp Lys Leu Glu Ile Leu 100 105 110 Gln Asn Gly Leu Tyr Leu Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn 115 120 125 Tyr Asn Asp Val Ala Pro Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp 130 135 140 Met Ile Gln Thr Leu Thr Asn Lys Ser Lys Ile Gln Asn Val Gly Gly 145 150 155 160 Thr Tyr Glu Leu His Val Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser 165 170 175 Glu His Gln Val Leu Lys Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu 180 185 190 Ala Asn Pro Gln Phe Ile Ser 195 <210> SEQ ID NO 2 <211> LENGTH: 173 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 2 Met Glu Glu Met Pro Leu Arg Glu Ser Ser Pro Gln Arg Ala Glu Arg 1 5 10 15 Cys Lys Lys Ser Trp Leu Leu Cys Ile Val Ala Leu Leu Leu Met Leu 20 25 30 Leu Cys Ser Leu Gly Thr Leu Ile Tyr Thr Ser Leu Lys Pro Thr Ala 35 40 45 Ile Glu Ser Cys Met Val Lys Phe Glu Leu Ser Ser Ser Lys Trp His 50 55 60 Met Thr Ser Pro Lys Pro His Cys Val Asn Thr Thr Ser Asp Gly Lys 65 70 75 80 Leu Lys Ile Leu Gln Ser Gly Thr Tyr Leu Ile Tyr Gly Gln Val Ile 85 90 95 Pro Val Asp Lys Lys Tyr Ile Lys Asp Asn Ala Pro Phe Val Val Gln 100 105 110 Ile Tyr Lys Lys Asn Asp Val Leu Gln Thr Leu Met Asn Asp Phe Gln 115 120 125 Ile Leu Pro Ile Gly Gly Val Tyr Glu Leu His Ala Gly Asp Asn Ile 130 135 140 Tyr Leu Lys Phe Asn Ser Lys Asp His Ile Gln Lys Thr Asn Thr Tyr 145 150 155 160 Trp Gly Ile Ile Leu Met Pro Asp Leu Pro Phe Ile Ser 165 170 <210> SEQ ID NO 3 <211> LENGTH: 288 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr 1 5 10 15 Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys 20 25 30 Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu 35 40 45 Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile 50 55 60 Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp 65 70 75 80 Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr 85 90 95 Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly 100 105 110 Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg 115 120 125 Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr 130 135 140 Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile 145 150 155 160 Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu 165 170 175 Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp 180 185 190 Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met 195 200 205 Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg 210 215 220 Val Asn Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro 225 230 235 240 Asp Asn Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly 245 250 255 Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg 260 265 270 Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val 275 280 285 <210> SEQ ID NO 4 <211> LENGTH: 233 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala 1 5 10 15 Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe 20 25 30 Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe 35 40 45 Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro 50 55 60 Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser 65 70 75 80 Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro 85 90 95 Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu 100 105 110 Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser 115 120 125 Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly 130 135 140 Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala 145 150 155 160 Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro 165 170 175 Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu 180 185 190 Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu 195 200 205 Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly 210 215 220 Gln Val Tyr Phe Gly Ile Ile Ala Leu 225 230 <210> SEQ ID NO 5 <211> LENGTH: 255 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 5 Met Ile Glu Thr Tyr Ser Gln Pro Ser Pro Arg Ser Val Ala Thr Gly 1 5 10 15 Leu Pro Ala Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Val Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp Phe Val 50 55 60 Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu Val Lys 85 90 95 Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asp Glu Asp Pro Val 100 105 110 Ala His Val Val Ala Asn His Gln Val Glu Glu Gln Leu Glu Trp Leu 115 120 125 Ser Gln Arg Ala Asn Ala Leu Leu Ala Asn Gly Met Asp Leu Lys Asp 130 135 140 Asn Gln Leu Val Val Pro Ala Asp Gly Leu Tyr Leu Val Tyr Ser Gln 145 150 155 160 Val Leu Phe Lys Gly Gln Gly Cys Pro Asp Tyr Val Leu Leu Thr His 165 170 175 Thr Val Ser Arg Phe Ala Ile Ser Tyr Gln Glu Lys Val Asn Leu Leu

180 185 190 Ser Ala Val Lys Ser Pro Cys Pro Lys Asp Thr Pro Glu Gly Ala Glu 195 200 205 Leu Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu 210 215 220 Glu Lys Gly Asp Gln Leu Ser Ala Glu Val Asn Leu Pro Lys Tyr Leu 225 230 235 240 Asp Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu 245 250 255 <210> SEQ ID NO 6 <211> LENGTH: 141 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 6 Met Trp Leu Gln Asn Leu Leu Phe Leu Gly Ile Val Val Tyr Ser Leu 1 5 10 15 Ser Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His 20 25 30 Val Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val 35 40 45 Thr Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys 50 55 60 Lys Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu 65 70 75 80 Arg Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser 85 90 95 Tyr Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr 100 105 110 Gln Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu 115 120 125 Thr Asp Ile Pro Phe Glu Cys Lys Lys Pro Gly Gln Lys 130 135 140 <210> SEQ ID NO 7 <211> LENGTH: 302 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 Met Arg Leu Gly Ser Pro Gly Leu Leu Phe Leu Leu Phe Ser Ser Leu 1 5 10 15 Arg Ala Asp Thr Gln Glu Lys Glu Val Arg Ala Met Val Gly Ser Asp 20 25 30 Val Glu Leu Ser Cys Ala Cys Pro Glu Gly Ser Arg Phe Asp Leu Asn 35 40 45 Asp Val Tyr Val Tyr Trp Gln Thr Ser Glu Ser Lys Thr Val Val Thr 50 55 60 Tyr His Ile Pro Gln Asn Ser Ser Leu Glu Asn Val Asp Ser Arg Tyr 65 70 75 80 Arg Asn Arg Ala Leu Met Ser Pro Ala Gly Met Leu Arg Gly Asp Phe 85 90 95 Ser Leu Arg Leu Phe Asn Val Thr Pro Gln Asp Glu Gln Lys Phe His 100 105 110 Cys Leu Val Leu Ser Gln Ser Leu Gly Phe Gln Glu Val Leu Ser Val 115 120 125 Glu Val Thr Leu His Val Ala Ala Asn Phe Ser Val Pro Val Val Ser 130 135 140 Ala Pro His Ser Pro Ser Gln Asp Glu Leu Thr Phe Thr Cys Thr Ser 145 150 155 160 Ile Asn Gly Tyr Pro Arg Pro Asn Val Tyr Trp Ile Asn Lys Thr Asp 165 170 175 Asn Ser Leu Leu Asp Gln Ala Leu Gln Asn Asp Thr Val Phe Leu Asn 180 185 190 Met Arg Gly Leu Tyr Asp Val Val Ser Val Leu Arg Ile Ala Arg Thr 195 200 205 Pro Ser Val Asn Ile Gly Cys Cys Ile Glu Asn Val Leu Leu Gln Gln 210 215 220 Asn Leu Thr Val Gly Ser Gln Thr Gly Asn Asp Ile Gly Glu Arg Asp 225 230 235 240 Lys Ile Thr Glu Asn Pro Val Ser Thr Gly Glu Lys Asn Ala Ala Thr 245 250 255 Trp Ser Ile Leu Ala Val Leu Cys Leu Leu Val Val Val Ala Val Ala 260 265 270 Ile Gly Trp Val Cys Arg Asp Arg Cys Leu Gln His Ser Tyr Ala Gly 275 280 285 Ala Trp Ala Val Ser Pro Glu Thr Glu Leu Thr Gly His Val 290 295 300 <210> SEQ ID NO 8 <211> LENGTH: 254 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Glu Tyr Ala Ser Asp Ala Ser Leu Asp Pro Glu Ala Pro Trp Pro 1 5 10 15 Pro Ala Pro Arg Ala Arg Ala Cys Arg Val Leu Pro Trp Ala Leu Val 20 25 30 Ala Gly Leu Leu Leu Leu Leu Leu Leu Ala Ala Ala Cys Ala Val Phe 35 40 45 Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser 50 55 60 Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp 65 70 75 80 Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val 85 90 95 Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp 100 105 110 Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu 115 120 125 Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe 130 135 140 Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser 145 150 155 160 Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala 165 170 175 Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala 180 185 190 Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala 195 200 205 Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His 210 215 220 Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val 225 230 235 240 Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu 245 250 <210> SEQ ID NO 9 <211> LENGTH: 277 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu 1 5 10 15 Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val 20 25 30 Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro 35 40 45 Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys 50 55 60 Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro 65 70 75 80 Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys 85 90 95 Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly 100 105 110 Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys 115 120 125 Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp 130 135 140 Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn 145 150 155 160 Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro 165 170 175 Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr 180 185 190 Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu 195 200 205 Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val 210 215 220 Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu 225 230 235 240 Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly 245 250 255 Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser 260 265 270 Thr Leu Ala Lys Ile 275 <210> SEQ ID NO 10 <211> LENGTH: 198 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 10 Met Glu Gly Glu Gly Val Gln Pro Leu Asp Glu Asn Leu Glu Asn Gly 1 5 10 15 Ser Arg Pro Arg Phe Lys Trp Lys Lys Thr Leu Arg Leu Val Val Ser 20 25 30 Gly Ile Lys Gly Ala Gly Met Leu Leu Cys Phe Ile Tyr Val Cys Leu 35 40 45 Gln Leu Ser Ser Ser Pro Ala Lys Asp Pro Pro Ile Gln Arg Leu Arg 50 55 60

Gly Ala Val Thr Arg Cys Glu Asp Gly Gln Leu Phe Ile Ser Ser Tyr 65 70 75 80 Lys Asn Glu Tyr Gln Thr Met Glu Val Gln Asn Asn Ser Val Val Ile 85 90 95 Lys Cys Asp Gly Leu Tyr Ile Ile Tyr Leu Lys Gly Ser Phe Phe Gln 100 105 110 Glu Val Lys Ile Asp Leu His Phe Arg Glu Asp His Asn Pro Ile Ser 115 120 125 Ile Pro Met Leu Asn Asp Gly Arg Arg Ile Val Phe Thr Val Val Ala 130 135 140 Ser Leu Ala Phe Lys Asp Lys Val Tyr Leu Thr Val Asn Ala Pro Asp 145 150 155 160 Thr Leu Cys Glu His Leu Gln Ile Asn Asp Gly Glu Leu Ile Val Val 165 170 175 Gln Leu Thr Pro Gly Tyr Cys Ala Pro Glu Gly Ser Tyr His Ser Thr 180 185 190 Val Asn Gln Val Pro Leu 195 <210> SEQ ID NO 11 <211> LENGTH: 261 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly 1 5 10 15 Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val 50 55 60 Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys 85 90 95 Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu 100 105 110 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 115 120 125 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 130 135 140 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 145 150 155 160 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 165 170 175 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 180 185 190 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 195 200 205 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 210 215 220 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 225 230 235 240 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 245 250 255 Gly Leu Leu Lys Leu 260 <210> SEQ ID NO 12 <211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 12 Met Ile Glu Thr Tyr Ser Gln Pro Ser Pro Arg Ser Val Ala Thr Gly 1 5 10 15 Leu Pro Ala Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Val Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Val Glu Glu Glu Val Asn Leu His Glu Asp Phe Val 50 55 60 Phe Ile Lys Lys Leu Lys Arg Cys Asn Lys Gly Glu Gly Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Met Arg Arg Gln Phe Glu Asp Leu Val Lys 85 90 95 Asp Ile Thr Leu Asn Lys Glu Glu Lys Lys Glu Asn Ser Phe Glu Met 100 105 110 Gln Arg Gly Asp Glu Asp Pro Gln Ile Ala Ala His Val Val Ser Glu 115 120 125 Ala Asn Ser Asn Ala Ala Ser Val Leu Gln Trp Ala Lys Lys Gly Tyr 130 135 140 Tyr Thr Met Lys Ser Asn Leu Val Met Leu Glu Asn Gly Lys Gln Leu 145 150 155 160 Thr Val Lys Arg Glu Gly Leu Tyr Tyr Val Tyr Thr Gln Val Thr Phe 165 170 175 Cys Ser Asn Arg Glu Pro Ser Ser Gln Arg Pro Phe Ile Val Gly Leu 180 185 190 Trp Leu Lys Pro Ser Ser Gly Ser Glu Arg Ile Leu Leu Lys Ala Ala 195 200 205 Asn Thr His Ser Ser Ser Gln Leu Cys Glu Gln Gln Ser Val His Leu 210 215 220 Gly Gly Val Phe Glu Leu Gln Ala Gly Ala Ser Val Phe Val Asn Val 225 230 235 240 Thr Glu Ala Ser Gln Val Ile His Arg Val Gly Phe Ser Ser Phe Gly 245 250 255 Leu Leu Lys Leu 260 <210> SEQ ID NO 13 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Val Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro <210> SEQ ID NO 14 <211> LENGTH: 195 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 14 Met Pro Glu Glu Gly Arg Pro Cys Pro Trp Val Arg Trp Ser Gly Thr 1 5 10 15 Ala Phe Gln Arg Gln Trp Pro Trp Leu Leu Leu Val Val Phe Ile Thr 20 25 30 Val Phe Cys Cys Trp Phe His Cys Ser Gly Leu Leu Ser Lys Gln Gln 35 40 45 Gln Arg Leu Leu Glu His Pro Glu Pro His Thr Ala Glu Leu Gln Leu 50 55 60 Asn Leu Thr Val Pro Arg Lys Asp Pro Thr Leu Arg Trp Gly Ala Gly 65 70 75 80 Pro Ala Leu Gly Arg Ser Phe Thr His Gly Pro Glu Leu Glu Glu Gly 85 90 95 His Leu Arg Ile His Gln Asp Gly Leu Tyr Arg Leu His Ile Gln Val 100 105 110 Thr Leu Ala Asn Cys Ser Ser Pro Gly Ser Thr Leu Gln His Arg Ala 115 120 125 Thr Leu Ala Val Gly Ile Cys Ser Pro Ala Ala His Gly Ile Ser Leu 130 135 140 Leu Arg Gly Arg Phe Gly Gln Asp Cys Thr Val Ala Leu Gln Arg Leu 145 150 155 160 Thr Tyr Leu Val His Gly Asp Val Leu Cys Thr Asn Leu Thr Leu Pro 165 170 175 Leu Leu Pro Ser Arg Asn Ala Asp Glu Thr Phe Phe Gly Val Gln Trp 180 185 190 Ile Cys Pro 195 <210> SEQ ID NO 15 <211> LENGTH: 153 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu 1 5 10 15 Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu

20 25 30 Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 35 40 45 Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 50 55 60 Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 65 70 75 80 Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 85 90 95 Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 100 105 110 Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 115 120 125 Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 130 135 140 Cys Gln Ser Ile Ile Ser Thr Leu Thr 145 150 <210> SEQ ID NO 16 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His <210> SEQ ID NO 17 <211> LENGTH: 154 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 17 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Ile Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Thr Ser Ser Glu Cys His Ile Lys Asp Lys 20 25 30 Glu Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu 35 40 45 Asp Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn 50 55 60 Phe Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu 65 70 75 80 Asn Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser 85 90 95 Glu Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr 100 105 110 Leu Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys 115 120 125 Lys Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr 130 135 140 Cys Trp Asn Lys Ile Leu Lys Gly Ser Ile 145 150 <210> SEQ ID NO 18 <211> LENGTH: 253 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Trp Pro Pro Gly Ser Ala Ser Gln Pro Pro Pro Ser Pro Ala Ala 1 5 10 15 Ala Thr Gly Leu His Pro Ala Ala Arg Pro Val Ser Leu Gln Cys Arg 20 25 30 Leu Ser Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val 35 40 45 Leu Leu Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro 50 55 60 Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg 65 70 75 80 Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr 85 90 95 Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys 100 105 110 Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu 115 120 125 Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys 130 135 140 Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser 145 150 155 160 Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn 165 170 175 Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn 180 185 190 Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser 195 200 205 Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys 210 215 220 Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala 225 230 235 240 Val Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 245 250 <210> SEQ ID NO 19 <211> LENGTH: 662 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 Met Glu Pro Leu Val Thr Trp Val Val Pro Leu Leu Phe Leu Phe Leu 1 5 10 15 Leu Ser Arg Gln Gly Ala Ala Cys Arg Thr Ser Glu Cys Cys Phe Gln 20 25 30 Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg 35 40 45 Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp 50 55 60 Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys 65 70 75 80 Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg 85 90 95 Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr 100 105 110 Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu 115 120 125 Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly 130 135 140 Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu 145 150 155 160 Thr Pro Asp Asn Gln Val Gly Ala Glu Val Gln Phe Arg His Arg Thr 165 170 175 Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp 180 185 190 Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe 195 200 205 Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys 210 215 220 Trp Ser Ser Pro Val Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln 225 230 235 240 Val Arg Phe Ser Val Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu 245 250 255 Thr Leu Lys Glu Gln Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln 260 265 270 Gly Leu Ala Pro Gly Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met 275 280 285 Leu Ser Cys Pro Cys Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly 290 295 300 Lys Met Pro Tyr Leu Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser 305 310 315 320 Ser Asn Gln Phe Gly Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala 325 330 335 Asp Thr His Thr Glu Pro Val Ala Leu Asn Ile Ser Val Gly Thr Asn 340 345 350 Gly Thr Thr Met Tyr Trp Pro Ala Arg Ala Gln Ser Met Thr Tyr Cys 355 360 365 Ile Glu Trp Gln Pro Val Gly Gln Asp Gly Gly Leu Ala Thr Cys Ser 370 375 380 Leu Thr Ala Pro Gln Asp Pro Asp Pro Ala Gly Met Ala Thr Tyr Ser 385 390 395 400 Trp Ser Arg Glu Ser Gly Ala Met Gly Gln Glu Lys Cys Tyr Tyr Ile 405 410 415 Thr Ile Phe Ala Ser Ala His Pro Glu Lys Leu Thr Leu Trp Ser Thr 420 425 430

Val Leu Ser Thr Tyr His Phe Gly Gly Asn Ala Ser Ala Ala Gly Thr 435 440 445 Pro His His Val Ser Val Lys Asn His Ser Leu Asp Ser Val Ser Val 450 455 460 Asp Trp Ala Pro Ser Leu Leu Ser Thr Cys Pro Gly Val Leu Lys Glu 465 470 475 480 Tyr Val Val Arg Cys Arg Asp Glu Asp Ser Lys Gln Val Ser Glu His 485 490 495 Pro Val Gln Pro Thr Glu Thr Gln Val Thr Leu Ser Gly Leu Arg Ala 500 505 510 Gly Val Ala Tyr Thr Val Gln Val Arg Ala Asp Thr Ala Trp Leu Arg 515 520 525 Gly Val Trp Ser Gln Pro Gln Arg Phe Ser Ile Glu Val Gln Val Ser 530 535 540 Asp Trp Leu Ile Phe Phe Ala Ser Leu Gly Ser Phe Leu Ser Ile Leu 545 550 555 560 Leu Val Gly Val Leu Gly Tyr Leu Gly Leu Asn Arg Ala Ala Arg His 565 570 575 Leu Cys Pro Pro Leu Pro Thr Pro Cys Ala Ser Ser Ala Ile Glu Phe 580 585 590 Pro Gly Gly Lys Glu Thr Trp Gln Trp Ile Asn Pro Val Asp Phe Gln 595 600 605 Glu Glu Ala Ser Leu Gln Glu Ala Leu Val Val Glu Met Ser Trp Asp 610 615 620 Lys Gly Glu Arg Thr Glu Pro Leu Glu Lys Thr Glu Leu Pro Glu Gly 625 630 635 640 Ala Pro Glu Leu Ala Leu Asp Thr Glu Leu Ser Leu Glu Asp Gly Asp 645 650 655 Arg Cys Lys Ala Lys Met 660 <210> SEQ ID NO 20 <211> LENGTH: 543 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 20 Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu 1 5 10 15 Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys 65 70 75 80 Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr 85 90 95 Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp 100 105 110 Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys 115 120 125 Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln 130 135 140 Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro 145 150 155 160 Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys 165 170 175 Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln 180 185 190 Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu 195 200 205 Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser 210 215 220 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 225 230 235 240 Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro 245 250 255 Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val 260 265 270 Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys 275 280 285 Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln 290 295 300 Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn 305 310 315 320 Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser Gly 325 330 335 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Val 340 345 350 Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu 355 360 365 Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys Leu Lys 370 375 380 His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile Thr Arg 385 390 395 400 Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu His Lys 405 410 415 Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly 420 425 430 Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu Cys Leu 435 440 445 Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala 450 455 460 Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile Leu Asp 465 470 475 480 Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu Asn His 485 490 495 Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala Asp Pro 500 505 510 Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe Ser Thr 515 520 525 Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser Ala 530 535 540 <210> SEQ ID NO 21 <211> LENGTH: 162 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Met Arg Ile Ser Lys Pro His Leu Arg Ser Ile Ser Ile Gln Cys Tyr 1 5 10 15 Leu Cys Leu Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His 20 25 30 Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys Thr Glu Ala 35 40 45 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 50 55 60 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 65 70 75 80 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 85 90 95 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 100 105 110 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 115 120 125 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 130 135 140 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 145 150 155 160 Thr Ser <210> SEQ ID NO 22 <211> LENGTH: 357 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 22 Met Lys Ile Leu Lys Pro Tyr Met Arg Asn Thr Ser Ile Ser Cys Tyr 1 5 10 15 Leu Cys Phe Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His 20 25 30 Val Phe Ile Leu Gly Cys Val Ser Val Gly Leu Pro Lys Thr Glu Ala 35 40 45 Asn Trp Ile Asp Val Arg Tyr Asp Leu Glu Lys Ile Glu Ser Leu Ile 50 55 60 Gln Ser Ile His Ile Asp Thr Thr Leu Tyr Thr Asp Ser Asp Phe His 65 70 75 80 Pro Ser Cys Lys Val Thr Ala Met Asn Cys Phe Leu Leu Glu Leu Gln 85 90 95 Val Ile Leu His Glu Tyr Ser Asn Met Thr Leu Asn Glu Thr Val Arg 100 105 110 Asn Val Leu Tyr Leu Ala Asn Ser Thr Leu Ser Ser Asn Lys Asn Val 115 120 125 Ala Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Thr Phe 130 135 140 Thr Glu Phe Leu Gln Ser Phe Ile Arg Ile Val Gln Met Phe Ile Asn 145 150 155 160 Thr Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly 165 170 175 Asp Val Glu Glu Asn Pro Gly Pro Gly Thr Thr Cys Pro Pro Pro Val 180 185 190 Ser Ile Glu His Ala Asp Ile Arg Val Lys Asn Tyr Ser Val Asn Ser 195 200 205 Arg Glu Arg Tyr Val Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr 210 215 220 Ser Thr Leu Ile Glu Cys Val Ile Asn Lys Asn Thr Asn Val Ala His 225 230 235 240 Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ser Leu Ala His 245 250 255

Tyr Ser Pro Val Pro Thr Val Val Thr Pro Lys Val Thr Ser Gln Pro 260 265 270 Glu Ser Pro Ser Pro Ser Ala Lys Glu Pro Glu Ala Phe Ser Pro Lys 275 280 285 Ser Asp Thr Ala Met Thr Thr Glu Thr Ala Ile Met Pro Gly Ser Arg 290 295 300 Leu Thr Pro Ser Gln Thr Thr Ser Ala Gly Thr Thr Gly Thr Gly Ser 305 310 315 320 His Lys Ser Ser Arg Ala Pro Ser Leu Ala Ala Thr Met Thr Leu Glu 325 330 335 Pro Thr Ala Ser Thr Ser Leu Arg Ile Thr Glu Ile Ser Pro His Ser 340 345 350 Ser Lys Met Thr Lys 355 <210> SEQ ID NO 23 <211> LENGTH: 578 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg 1 5 10 15 Leu Gly Ser Asp Ala His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val 20 25 30 Trp Phe Glu Ala Glu Phe Phe His His Ile Leu His Trp Thr Pro Ile 35 40 45 Pro Asn Gln Ser Glu Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr 50 55 60 Gly Ile Glu Ser Trp Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser 65 70 75 80 Tyr Asp Leu Thr Ala Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr 85 90 95 Arg Ala Arg Val Arg Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr 100 105 110 Val Thr Asn Thr Arg Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly 115 120 125 Ser Val Asn Leu Glu Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln 130 135 140 Leu Pro Arg Pro Lys Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile 145 150 155 160 Phe Ser His Phe Arg Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly 165 170 175 Asn Phe Thr Phe Thr His Lys Lys Val Lys His Glu Asn Phe Ser Leu 180 185 190 Leu Thr Ser Gly Glu Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser 195 200 205 Val Ala Ser Arg Ser Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile 210 215 220 Ser Leu Thr Arg Gln Tyr Phe Thr Val Thr Asn Val Ile Ile Phe Phe 225 230 235 240 Ala Phe Val Leu Leu Leu Ser Gly Ala Leu Ala Tyr Cys Leu Ala Leu 245 250 255 Gln Leu Tyr Val Arg Arg Arg Lys Lys Leu Pro Ser Val Leu Leu Phe 260 265 270 Lys Lys Pro Ser Pro Phe Ile Phe Ile Ser Gln Arg Pro Ser Pro Glu 275 280 285 Thr Gln Asp Thr Ile His Pro Leu Asp Glu Glu Ala Phe Leu Lys Val 290 295 300 Ser Pro Glu Leu Lys Asn Leu Asp Leu His Gly Ser Thr Asp Ser Gly 305 310 315 320 Phe Gly Ser Thr Lys Pro Ser Leu Gln Thr Glu Glu Pro Gln Phe Leu 325 330 335 Leu Pro Asp Pro His Pro Gln Ala Asp Arg Thr Leu Gly Asn Arg Glu 340 345 350 Pro Pro Val Leu Gly Asp Ser Cys Ser Ser Gly Ser Ser Asn Ser Thr 355 360 365 Asp Ser Gly Ile Cys Leu Gln Glu Pro Ser Leu Ser Pro Ser Thr Gly 370 375 380 Pro Thr Trp Glu Gln Gln Val Gly Ser Asn Ser Arg Gly Gln Asp Asp 385 390 395 400 Ser Gly Ile Asp Leu Val Gln Asn Ser Glu Gly Arg Ala Gly Asp Thr 405 410 415 Gln Gly Gly Ser Ala Leu Gly His His Ser Pro Pro Glu Pro Glu Val 420 425 430 Pro Gly Glu Glu Asp Pro Ala Ala Val Ala Phe Gln Gly Tyr Leu Arg 435 440 445 Gln Thr Arg Cys Ala Glu Glu Lys Ala Thr Lys Thr Gly Cys Leu Glu 450 455 460 Glu Glu Ser Pro Leu Thr Asp Gly Leu Gly Pro Lys Phe Gly Arg Cys 465 470 475 480 Leu Val Asp Glu Ala Gly Leu His Pro Pro Ala Leu Ala Lys Gly Tyr 485 490 495 Leu Lys Gln Asp Pro Leu Glu Met Thr Leu Ala Ser Ser Gly Ala Pro 500 505 510 Thr Gly Gln Trp Asn Gln Pro Thr Glu Glu Trp Ser Leu Leu Ala Leu 515 520 525 Ser Ser Cys Ser Asp Leu Gly Ile Ser Asp Trp Ser Phe Ala His Asp 530 535 540 Leu Ala Pro Leu Gly Cys Val Ala Ala Pro Gly Gly Leu Leu Gly Ser 545 550 555 560 Phe Asn Ser Asp Leu Val Thr Leu Pro Leu Ile Ser Ser Leu Gln Ser 565 570 575 Ser Glu <210> SEQ ID NO 24 <211> LENGTH: 479 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 24 Met Leu Ser Arg Leu Leu Pro Phe Leu Val Thr Ile Ser Ser Leu Ser 1 5 10 15 Leu Glu Phe Ile Ala Tyr Gly Thr Glu Leu Pro Ser Pro Ser Tyr Val 20 25 30 Trp Phe Glu Ala Arg Phe Phe Gln His Ile Leu His Trp Lys Pro Ile 35 40 45 Pro Asn Gln Ser Glu Ser Thr Tyr Tyr Glu Val Ala Leu Lys Gln Tyr 50 55 60 Gly Asn Ser Thr Trp Asn Asp Ile His Ile Cys Arg Lys Ala Gln Ala 65 70 75 80 Leu Ser Cys Asp Leu Thr Thr Phe Thr Leu Asp Leu Tyr His Arg Ser 85 90 95 Tyr Gly Tyr Arg Ala Arg Val Arg Ala Val Asp Asn Ser Gln Tyr Ser 100 105 110 Asn Trp Thr Thr Thr Glu Thr Arg Phe Thr Val Asp Glu Val Ile Leu 115 120 125 Thr Val Asp Ser Val Thr Leu Lys Ala Met Asp Gly Ile Ile Tyr Gly 130 135 140 Thr Ile His Pro Pro Arg Pro Thr Ile Thr Pro Ala Gly Asp Glu Tyr 145 150 155 160 Glu Gln Val Phe Lys Asp Leu Arg Val Tyr Lys Ile Ser Ile Arg Lys 165 170 175 Phe Ser Glu Leu Lys Asn Ala Thr Lys Arg Val Lys Gln Glu Thr Phe 180 185 190 Thr Leu Thr Val Pro Ile Gly Val Arg Lys Phe Cys Val Lys Val Leu 195 200 205 Pro Arg Leu Glu Ser Arg Ile Asn Lys Ala Glu Trp Ser Glu Glu Gln 210 215 220 Cys Leu Leu Ile Thr Thr Glu Gln Tyr Phe Thr Val Thr Asn Leu Ser 225 230 235 240 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 245 250 255 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 260 265 270 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 275 280 285 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 290 295 300 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 305 310 315 320 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 325 330 335 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 340 345 350 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 370 375 380 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 385 390 395 400 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 405 410 415 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 420 425 430 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 435 440 445 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 450 455 460 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 465 470 475 <210> SEQ ID NO 25 <211> LENGTH: 636 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 Met Arg Gly Gly Arg Gly Ala Pro Phe Trp Leu Trp Pro Leu Pro Lys 1 5 10 15 Leu Ala Leu Leu Pro Leu Leu Trp Val Leu Phe Gln Arg Thr Arg Pro 20 25 30

Gln Gly Ser Ala Gly Pro Leu Gln Cys Tyr Gly Val Gly Pro Leu Gly 35 40 45 Asp Leu Asn Cys Ser Trp Glu Pro Leu Gly Asp Leu Gly Ala Pro Ser 50 55 60 Glu Leu His Leu Gln Ser Gln Lys Tyr Arg Ser Asn Lys Thr Gln Thr 65 70 75 80 Val Ala Val Ala Ala Gly Arg Ser Trp Val Ala Ile Pro Arg Glu Gln 85 90 95 Leu Thr Met Ser Asp Lys Leu Leu Val Trp Gly Thr Lys Ala Gly Gln 100 105 110 Pro Leu Trp Pro Pro Val Phe Val Asn Leu Glu Thr Gln Met Lys Pro 115 120 125 Asn Ala Pro Arg Leu Gly Pro Asp Val Asp Phe Ser Glu Asp Asp Pro 130 135 140 Leu Glu Ala Thr Val His Trp Ala Pro Pro Thr Trp Pro Ser His Lys 145 150 155 160 Val Leu Ile Cys Gln Phe His Tyr Arg Arg Cys Gln Glu Ala Ala Trp 165 170 175 Thr Leu Leu Glu Pro Glu Leu Lys Thr Ile Pro Leu Thr Pro Val Glu 180 185 190 Ile Gln Asp Leu Glu Leu Ala Thr Gly Tyr Lys Val Tyr Gly Arg Cys 195 200 205 Arg Met Glu Lys Glu Glu Asp Leu Trp Gly Glu Trp Ser Pro Ile Leu 210 215 220 Ser Phe Gln Thr Pro Pro Ser Ala Pro Lys Asp Val Trp Val Ser Gly 225 230 235 240 Asn Leu Cys Gly Thr Pro Gly Gly Glu Glu Pro Leu Leu Leu Trp Lys 245 250 255 Ala Pro Gly Pro Cys Val Gln Val Ser Tyr Lys Val Trp Phe Trp Val 260 265 270 Gly Gly Arg Glu Leu Ser Pro Glu Gly Ile Thr Cys Cys Cys Ser Leu 275 280 285 Ile Pro Ser Gly Ala Glu Trp Ala Arg Val Ser Ala Val Asn Ala Thr 290 295 300 Ser Trp Glu Pro Leu Thr Asn Leu Ser Leu Val Cys Leu Asp Ser Ala 305 310 315 320 Ser Ala Pro Arg Ser Val Ala Val Ser Ser Ile Ala Gly Ser Thr Glu 325 330 335 Leu Leu Val Thr Trp Gln Pro Gly Pro Gly Glu Pro Leu Glu His Val 340 345 350 Val Asp Trp Ala Arg Asp Gly Asp Pro Leu Glu Lys Leu Asn Trp Val 355 360 365 Arg Leu Pro Pro Gly Asn Leu Ser Ala Leu Leu Pro Gly Asn Phe Thr 370 375 380 Val Gly Val Pro Tyr Arg Ile Thr Val Thr Ala Val Ser Ala Ser Gly 385 390 395 400 Leu Ala Ser Ala Ser Ser Val Trp Gly Phe Arg Glu Glu Leu Ala Pro 405 410 415 Leu Val Gly Pro Thr Leu Trp Arg Leu Gln Asp Ala Pro Pro Gly Thr 420 425 430 Pro Ala Ile Ala Trp Gly Glu Val Pro Arg His Gln Leu Arg Gly His 435 440 445 Leu Thr His Tyr Thr Leu Cys Ala Gln Ser Gly Thr Ser Pro Ser Val 450 455 460 Cys Met Asn Val Ser Gly Asn Thr Gln Ser Val Thr Leu Pro Asp Leu 465 470 475 480 Pro Trp Gly Pro Cys Glu Leu Trp Val Thr Ala Ser Thr Ile Ala Gly 485 490 495 Gln Gly Pro Pro Gly Pro Ile Leu Arg Leu His Leu Pro Asp Asn Thr 500 505 510 Leu Arg Trp Lys Val Leu Pro Gly Ile Leu Phe Leu Trp Gly Leu Phe 515 520 525 Leu Leu Gly Cys Gly Leu Ser Leu Ala Thr Ser Gly Arg Cys Tyr His 530 535 540 Leu Arg His Lys Val Leu Pro Arg Trp Val Trp Glu Lys Val Pro Asp 545 550 555 560 Pro Ala Asn Ser Ser Ser Gly Gln Pro His Met Glu Gln Val Pro Glu 565 570 575 Ala Gln Pro Leu Gly Asp Leu Pro Ile Leu Glu Val Glu Glu Met Glu 580 585 590 Pro Pro Pro Val Met Glu Ser Ser Gln Pro Ala Gln Ala Thr Ala Pro 595 600 605 Leu Asp Ser Gly Tyr Glu Lys His Phe Leu Pro Thr Pro Glu Glu Leu 610 615 620 Gly Leu Leu Gly Pro Pro Arg Pro Gln Val Leu Ala 625 630 635 <210> SEQ ID NO 26 <211> LENGTH: 81 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu 1 5 10 15 Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln 20 25 30 Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe 35 40 45 Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val 50 55 60 Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly Arg Phe 65 70 75 80 Asn <210> SEQ ID NO 27 <211> LENGTH: 155 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Met Thr Pro Gly Lys Thr Ser Leu Val Ser Leu Leu Leu Leu Leu Ser 1 5 10 15 Leu Glu Ala Ile Val Lys Ala Gly Ile Thr Ile Pro Arg Asn Pro Gly 20 25 30 Cys Pro Asn Ser Glu Asp Lys Asn Phe Pro Arg Thr Val Met Val Asn 35 40 45 Leu Asn Ile His Asn Arg Asn Thr Asn Thr Asn Pro Lys Arg Ser Ser 50 55 60 Asp Tyr Tyr Asn Arg Ser Thr Ser Pro Trp Asn Leu His Arg Asn Glu 65 70 75 80 Asp Pro Glu Arg Tyr Pro Ser Val Ile Trp Glu Ala Lys Cys Arg His 85 90 95 Leu Gly Cys Ile Asn Ala Asp Gly Asn Val Asp Tyr His Met Asn Ser 100 105 110 Val Pro Ile Gln Gln Glu Ile Leu Val Leu Arg Arg Glu Pro Pro His 115 120 125 Cys Pro Asn Ser Phe Arg Leu Glu Lys Ile Leu Val Ser Val Gly Cys 130 135 140 Thr Cys Val Thr Pro Ile Val His His Val Ala 145 150 155 <210> SEQ ID NO 28 <211> LENGTH: 270 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> SEQ ID NO 29 <211> LENGTH: 270 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30

Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> SEQ ID NO 30 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser 115 120 125 Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu 130 135 140 Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser 145 150 155 160 Val Glu Leu His Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe 165 170 175 Val Leu His Asn Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr 180 185 190 Asp Pro Gly Val Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile 195 200 205 Lys Val Asp Ser Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys 210 215 220 Leu Ser Glu Thr 225 <210> SEQ ID NO 31 <211> LENGTH: 144 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Asn Lys 20 25 30 Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly 35 40 45 Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys 50 55 60 Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His 65 70 75 80 Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn 85 90 95 Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val 100 105 110 Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser 115 120 125 Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 130 135 140 <210> SEQ ID NO 32 <211> LENGTH: 264 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr Tyr Asn Asp Gln Ser Ile 115 120 125 Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu Ile Tyr Val Glu Asp Leu 130 135 140 Lys Lys Asp Glu Lys Lys Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser 145 150 155 160 Gln His Pro Ser Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu 165 170 175 Met Val Thr Leu Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn 180 185 190 Lys Glu His Ser Val Glu Leu His Lys Cys Glu Lys Pro Leu Pro Asp 195 200 205 Gln Ala Phe Phe Val Leu His Asn Met His Ser Asn Cys Val Ser Phe 210 215 220 Glu Cys Lys Thr Asp Pro Gly Val Phe Ile Gly Val Lys Asp Asn His 225 230 235 240 Leu Ala Leu Ile Lys Val Asp Ser Ser Glu Asn Leu Cys Thr Glu Asn 245 250 255 Ile Leu Phe Lys Leu Ser Glu Thr 260 <210> SEQ ID NO 33 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Ile Ser Pro Ile Thr Glu Tyr 65 70 75 80 Leu Ala Ser Leu Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu 85 90 95 Glu Asp Glu Ser Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu 100 105 110 Lys Lys Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser 115 120 125 Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu 130 135 140 Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser 145 150 155 160 Val Glu Leu His Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe 165 170 175 Val Leu His Asn Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr 180 185 190 Asp Pro Gly Val Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile 195 200 205 Lys Val Asp Ser Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys 210 215 220 Leu Ser Glu Thr 225 <210> SEQ ID NO 34 <211> LENGTH: 166 <212> TYPE: PRT <213> ORGANISM: Homo sapiens

<400> SEQUENCE: 34 Met Lys Tyr Thr Ser Tyr Ile Leu Ala Phe Gln Leu Cys Ile Val Leu 1 5 10 15 Gly Ser Leu Gly Cys Tyr Cys Gln Asp Pro Tyr Val Lys Glu Ala Glu 20 25 30 Asn Leu Lys Lys Tyr Phe Asn Ala Gly His Ser Asp Val Ala Asp Asn 35 40 45 Gly Thr Leu Phe Leu Gly Ile Leu Lys Asn Trp Lys Glu Glu Ser Asp 50 55 60 Arg Lys Ile Met Gln Ser Gln Ile Val Ser Phe Tyr Phe Lys Leu Phe 65 70 75 80 Lys Asn Phe Lys Asp Asp Gln Ser Ile Gln Lys Ser Val Glu Thr Ile 85 90 95 Lys Glu Asp Met Asn Val Lys Phe Phe Asn Ser Asn Lys Lys Lys Arg 100 105 110 Asp Asp Phe Glu Lys Leu Thr Asn Tyr Ser Val Thr Asp Leu Asn Val 115 120 125 Gln Arg Lys Ala Ile His Glu Leu Ile Gln Val Met Ala Glu Leu Ser 130 135 140 Pro Ala Ala Lys Thr Gly Lys Arg Lys Arg Ser Gln Met Leu Phe Arg 145 150 155 160 Gly Arg Arg Ala Ser Gln 165 <210> SEQ ID NO 35 <211> LENGTH: 495 <212> TYPE: PRT <213> ORGANISM: Salmonella enterica <400> SEQUENCE: 35 Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn 1 5 10 15 Asn Leu Asn Lys Ser Gln Ser Ala Leu Gly Thr Ala Ile Glu Arg Leu 20 25 30 Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45 Ala Ile Ala Asn Arg Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 65 70 75 80 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala 85 90 95 Val Gln Ser Ala Asn Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile 100 105 110 Gln Ala Glu Ile Thr Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly 115 120 125 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu 130 135 140 Thr Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu 145 150 155 160 Lys Gln Ile Asn Ser Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln 165 170 175 Gln Lys Tyr Lys Val Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala 180 185 190 Asp Thr Thr Ile Ala Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr 195 200 205 Gly Leu Gly Gly Thr Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp 210 215 220 Asp Thr Thr Gly Lys Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Thr 225 230 235 240 Gly Lys Asp Gly Tyr Tyr Glu Val Ser Val Asp Lys Thr Asn Gly Glu 245 250 255 Val Thr Leu Ala Gly Gly Ala Thr Ser Pro Leu Thr Gly Gly Leu Pro 260 265 270 Ala Thr Ala Thr Glu Asp Val Lys Asn Val Gln Val Ala Asn Ala Asp 275 280 285 Leu Thr Glu Ala Lys Ala Ala Leu Thr Ala Ala Gly Val Thr Gly Thr 290 295 300 Ala Ser Val Val Lys Met Ser Tyr Thr Asp Asn Asn Gly Lys Thr Ile 305 310 315 320 Asp Gly Gly Leu Ala Val Lys Val Gly Asp Asp Tyr Tyr Ser Ala Thr 325 330 335 Gln Asn Lys Asp Gly Ser Ile Ser Ile Asn Thr Thr Lys Tyr Thr Ala 340 345 350 Asp Asp Gly Thr Ser Lys Thr Ala Leu Asn Lys Leu Gly Gly Ala Asp 355 360 365 Gly Lys Thr Glu Val Val Ser Ile Gly Gly Lys Thr Tyr Ala Ala Ser 370 375 380 Lys Ala Glu Gly His Asn Phe Lys Ala Gln Pro Asp Leu Ala Glu Ala 385 390 395 400 Ala Ala Thr Thr Thr Glu Asn Pro Leu Gln Lys Ile Asp Ala Ala Leu 405 410 415 Ala Gln Val Asp Thr Leu Arg Ser Asp Leu Gly Ala Val Gln Asn Arg 420 425 430 Phe Asn Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Asn Asn Leu Thr 435 440 445 Ser Ala Arg Ser Arg Ile Glu Asp Ser Asp Tyr Ala Thr Glu Val Ser 450 455 460 Asn Met Ser Arg Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 465 470 475 480 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 485 490 495 <210> SEQ ID NO 36 <211> LENGTH: 507 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 36 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Thr Thr Leu Ser 20 25 30 Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn 65 70 75 80 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Gly 130 135 140 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Glu Ala Lys 145 150 155 160 Leu Gln Glu Ser Gly Pro Val Leu Val Lys Pro Gly Ala Ser Val Lys 165 170 175 Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met Asn 180 185 190 Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Val Ile 195 200 205 Asn Pro Tyr Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys 210 215 220 Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu 225 230 235 240 Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr 245 250 255 Tyr Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Ile Thr Val 260 265 270 Ser Thr Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys 275 280 285 Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro 290 295 300 Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr 305 310 315 320 Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser 325 330 335 Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His 340 345 350 Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile 355 360 365 Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn 370 375 380 Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys 385 390 395 400 Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu 405 410 415 Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe 420 425 430 Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu 435 440 445 Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr 450 455 460 Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg 465 470 475 480 Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His 485 490 495 Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 500 505 <210> SEQ ID NO 37 <211> LENGTH: 955 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 37

tatcaccctt gctaatcact cctcacagtg acctcaagtc ctgcaggcat gtacagcatg 60 cagctcgcat cctgtgtcac attgacactt gtgctccttg tcaacagcgc acccacttca 120 agctccactt caagctctac agcggaagca cagcagcagc agcagcagca gcagcagcag 180 cagcagcacc tggagcagct gttgatggac ctacaggagc tcctgagcag gatggagaat 240 tacaggaacc tgaaactccc caggatgctc accttcaaat tttacttgcc caagcaggcc 300 acagaattga aagatcttca gtgcctagaa gatgaacttg gacctctgcg gcatgttctg 360 gatttgactc aaagcaaaag ctttcaattg gaagatgctg agaatttcat cagcaatatc 420 agagtaactg ttgtaaaact aaagggctct gacaacacat ttgagtgcca attcgatgat 480 gagtcagcaa ctgtggtgga ctttctgagg agatggatag ccttctgtca aagcatcatc 540 tcaacaagcc ctcaataact atgtacctcc tgcttacaac acataaggct ctctatttat 600 ttaaatattt aactttaatt tatttttgga tgtattgttt actatctttt gtaactacta 660 gtcttcagat gataaatatg gatctttaaa gattcttttt gtaagcccca agggctcaaa 720 aatgttttaa actatttatc tgaaattatt tattatattg aattgttaaa tatcatgtgt 780 aggtagactc attaataaaa gtatttagat gattcaaata taaataagct cagatgtctg 840 tcatttttag gacagcacaa agtaagcgct aaaataactt ctcagttatt cctgtgaact 900 ctatgttaat cagtgttttc aagaaataaa gctctcctct aaaaaaaaaa aaaaa 955 <210> SEQ ID NO 38 <211> LENGTH: 169 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 38 Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu 1 5 10 15 Leu Val Asn Ser Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser Thr Ala 20 25 30 Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Leu 35 40 45 Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser Arg Met Glu Asn 50 55 60 Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe Lys Phe Tyr Leu 65 70 75 80 Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu Asp Glu 85 90 95 Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln Ser Lys Ser Phe 100 105 110 Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile Arg Val Thr Val 115 120 125 Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe Asp Asp 130 135 140 Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp Ile Ala Phe Cys 145 150 155 160 Gln Ser Ile Ile Ser Thr Ser Pro Gln 165 <210> SEQ ID NO 39 <211> LENGTH: 525 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 39 agcccagcaa gacctcagcc atgagacttc tcctcctgac tttcctggga gtctgctgcc 60 tcaccccatg ggttgtggaa ggtgtgggga ctgaagtcct agaagagagt agctgtgtga 120 acttacaaac ccagcggctg ccagttcaaa aaatcaagac ctatatcatc tgggaggggg 180 ccatgagagc tgtaattttt gtcaccaaac gaggactaaa aatttgtgct gatccagaag 240 ccaaatgggt gaaagcagcg atcaagactg tggatggcag ggccagtacc agaaagaaca 300 tggctgaaac tgttcccaca ggagcccaga ggtccaccag cacagcgata accctgactg 360 ggtaacagcc tccaggacaa tgtttcctca ctcgttaagc agctcatctc agttcccaaa 420 cccattgcac aaatacttat ttttattttt aacgacattc acattcattt caaatgttat 480 aagtaataaa tatttattat tgatgaaaaa aaaaaaaaaa aaaaa 525 <210> SEQ ID NO 40 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 40 Met Arg Leu Leu Leu Leu Thr Phe Leu Gly Val Cys Cys Leu Thr Pro 1 5 10 15 Trp Val Val Glu Gly Val Gly Thr Glu Val Leu Glu Glu Ser Ser Cys 20 25 30 Val Asn Leu Gln Thr Gln Arg Leu Pro Val Gln Lys Ile Lys Thr Tyr 35 40 45 Ile Ile Trp Glu Gly Ala Met Arg Ala Val Ile Phe Val Thr Lys Arg 50 55 60 Gly Leu Lys Ile Cys Ala Asp Pro Glu Ala Lys Trp Val Lys Ala Ala 65 70 75 80 Ile Lys Thr Val Asp Gly Arg Ala Ser Thr Arg Lys Asn Met Ala Glu 85 90 95 Thr Val Pro Thr Gly Ala Gln Arg Ser Thr Ser Thr Ala Ile Thr Leu 100 105 110 Thr Gly <210> SEQ ID NO 41 <211> LENGTH: 1028 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 41 gagacgtgca ctgaccgacc gtggtaatgg accagcacac acttgatgtg gaggataccg 60 cggatgccag acatccagca ggtacttcgt gcccctcgga tgcggcgctc ctcagagata 120 ccgggctcct cgcggacgct gcgctcctct cagatactgt gcgccccaca aatgccgcgc 180 tccccacgga tgctgcctac cctgcggtta atgttcggga tcgcgaggcc gcgtggccgc 240 ctgcactgaa cttctgttcc cgccacccaa agctctatgg cctagtcgct ttggttttgc 300 tgcttctgat cgccgcctgt gttcctatct tcacccgcac cgagcctcgg ccagcgctca 360 caatcaccac ctcgcccaac ctgggtaccc gagagaataa tgcagaccag gtcacccctg 420 tttcccacat tggctgcccc aacactacac aacagggctc tcctgtgttc gccaagctac 480 tggctaaaaa ccaagcatcg ttgtgcaata caactctgaa ctggcacagc caagatggag 540 ctgggagctc atacctatct caaggtctga ggtacgaaga agacaaaaag gagttggtgg 600 tagacagtcc cgggctctac tacgtatttt tggaactgaa gctcagtcca acattcacaa 660 acacaggcca caaggtgcag ggctgggtct ctcttgtttt gcaagcaaag cctcaggtag 720 atgactttga caacttggcc ctgacagtgg aactgttccc ttgctccatg gagaacaagt 780 tagtggaccg ttcctggagt caactgttgc tcctgaaggc tggccaccgc ctcagtgtgg 840 gtctgagggc ttatctgcat ggagcccagg atgcatacag agactgggag ctgtcttatc 900 ccaacaccac cagctttgga ctctttcttg tgaaacccga caacccatgg gaatgagaac 960 tatccttctt gtgactccta gttgctaagt cctcaagctg ctatgtttta tggggtctga 1020 gcaggggt 1028 <210> SEQ ID NO 42 <211> LENGTH: 309 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 42 Met Asp Gln His Thr Leu Asp Val Glu Asp Thr Ala Asp Ala Arg His 1 5 10 15 Pro Ala Gly Thr Ser Cys Pro Ser Asp Ala Ala Leu Leu Arg Asp Thr 20 25 30 Gly Leu Leu Ala Asp Ala Ala Leu Leu Ser Asp Thr Val Arg Pro Thr 35 40 45 Asn Ala Ala Leu Pro Thr Asp Ala Ala Tyr Pro Ala Val Asn Val Arg 50 55 60 Asp Arg Glu Ala Ala Trp Pro Pro Ala Leu Asn Phe Cys Ser Arg His 65 70 75 80 Pro Lys Leu Tyr Gly Leu Val Ala Leu Val Leu Leu Leu Leu Ile Ala 85 90 95 Ala Cys Val Pro Ile Phe Thr Arg Thr Glu Pro Arg Pro Ala Leu Thr 100 105 110 Ile Thr Thr Ser Pro Asn Leu Gly Thr Arg Glu Asn Asn Ala Asp Gln 115 120 125 Val Thr Pro Val Ser His Ile Gly Cys Pro Asn Thr Thr Gln Gln Gly 130 135 140 Ser Pro Val Phe Ala Lys Leu Leu Ala Lys Asn Gln Ala Ser Leu Cys 145 150 155 160 Asn Thr Thr Leu Asn Trp His Ser Gln Asp Gly Ala Gly Ser Ser Tyr 165 170 175 Leu Ser Gln Gly Leu Arg Tyr Glu Glu Asp Lys Lys Glu Leu Val Val 180 185 190 Asp Ser Pro Gly Leu Tyr Tyr Val Phe Leu Glu Leu Lys Leu Ser Pro 195 200 205 Thr Phe Thr Asn Thr Gly His Lys Val Gln Gly Trp Val Ser Leu Val 210 215 220 Leu Gln Ala Lys Pro Gln Val Asp Asp Phe Asp Asn Leu Ala Leu Thr 225 230 235 240 Val Glu Leu Phe Pro Cys Ser Met Glu Asn Lys Leu Val Asp Arg Ser 245 250 255 Trp Ser Gln Leu Leu Leu Leu Lys Ala Gly His Arg Leu Ser Val Gly 260 265 270 Leu Arg Ala Tyr Leu His Gly Ala Gln Asp Ala Tyr Arg Asp Trp Glu 275 280 285 Leu Ser Tyr Pro Asn Thr Thr Ser Phe Gly Leu Phe Leu Val Lys Pro 290 295 300 Asp Asn Pro Trp Glu 305 <210> SEQ ID NO 43 <211> LENGTH: 273 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic

polypeptide <400> SEQUENCE: 43 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Arg Thr Glu Pro Arg Pro Ala Leu Thr Ile Thr Thr Ser 65 70 75 80 Pro Asn Leu Gly Thr Arg Glu Asn Asn Ala Asp Gln Val Thr Pro Val 85 90 95 Ser His Ile Gly Cys Pro Asn Thr Thr Gln Gln Gly Ser Pro Val Phe 100 105 110 Ala Lys Leu Leu Ala Lys Asn Gln Ala Ser Leu Cys Asn Thr Thr Leu 115 120 125 Asn Trp His Ser Gln Asp Gly Ala Gly Ser Ser Tyr Leu Ser Gln Gly 130 135 140 Leu Arg Tyr Glu Glu Asp Lys Lys Glu Leu Val Val Asp Ser Pro Gly 145 150 155 160 Leu Tyr Tyr Val Phe Leu Glu Leu Lys Leu Ser Pro Thr Phe Thr Asn 165 170 175 Thr Gly His Lys Val Gln Gly Trp Val Ser Leu Val Leu Gln Ala Lys 180 185 190 Pro Gln Val Asp Asp Phe Asp Asn Leu Ala Leu Thr Val Glu Leu Phe 195 200 205 Pro Cys Ser Met Glu Asn Lys Leu Val Asp Arg Ser Trp Ser Gln Leu 210 215 220 Leu Leu Leu Lys Ala Gly His Arg Leu Ser Val Gly Leu Arg Ala Tyr 225 230 235 240 Leu His Gly Ala Gln Asp Ala Tyr Arg Asp Trp Glu Leu Ser Tyr Pro 245 250 255 Asn Thr Thr Ser Phe Gly Leu Phe Leu Val Lys Pro Asp Asn Pro Trp 260 265 270 Glu <210> SEQ ID NO 44 <211> LENGTH: 206 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 44 Arg Thr Glu Pro Arg Pro Ala Leu Thr Ile Thr Thr Ser Pro Asn Leu 1 5 10 15 Gly Thr Arg Glu Asn Asn Ala Asp Gln Val Thr Pro Val Ser His Ile 20 25 30 Gly Cys Pro Asn Thr Thr Gln Gln Gly Ser Pro Val Phe Ala Lys Leu 35 40 45 Leu Ala Lys Asn Gln Ala Ser Leu Cys Asn Thr Thr Leu Asn Trp His 50 55 60 Ser Gln Asp Gly Ala Gly Ser Ser Tyr Leu Ser Gln Gly Leu Arg Tyr 65 70 75 80 Glu Glu Asp Lys Lys Glu Leu Val Val Asp Ser Pro Gly Leu Tyr Tyr 85 90 95 Val Phe Leu Glu Leu Lys Leu Ser Pro Thr Phe Thr Asn Thr Gly His 100 105 110 Lys Val Gln Gly Trp Val Ser Leu Val Leu Gln Ala Lys Pro Gln Val 115 120 125 Asp Asp Phe Asp Asn Leu Ala Leu Thr Val Glu Leu Phe Pro Cys Ser 130 135 140 Met Glu Asn Lys Leu Val Asp Arg Ser Trp Ser Gln Leu Leu Leu Leu 145 150 155 160 Lys Ala Gly His Arg Leu Ser Val Gly Leu Arg Ala Tyr Leu His Gly 165 170 175 Ala Gln Asp Ala Tyr Arg Asp Trp Glu Leu Ser Tyr Pro Asn Thr Thr 180 185 190 Ser Phe Gly Leu Phe Leu Val Lys Pro Asp Asn Pro Trp Glu 195 200 205 <210> SEQ ID NO 45 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 45 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> SEQ ID NO 46 <211> LENGTH: 540 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 46 Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe 115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu 180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile 195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr 210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr 260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg 275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala 290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly 325 330 335 Gly Ser Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp 340 345 350 Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala 355 360 365 Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro 370 375 380 Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr 385 390 395 400 Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser 405 410 415 Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu 420 425 430 Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile 435 440 445 Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala 450 455 460 Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met 465 470 475 480 Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu 485 490 495 Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr 500 505 510 Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val 515 520 525 Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 530 535 540 <210> SEQ ID NO 47 <211> LENGTH: 328 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47 Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln

50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe 115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu 180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile 195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr 210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr 260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg 275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala 290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser 325 <210> SEQ ID NO 48 <211> LENGTH: 197 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48 Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu 1 5 10 15 His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys 20 25 30 Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp 35 40 45 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 50 55 60 Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr 65 70 75 80 Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 85 90 95 Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100 105 110 Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115 120 125 Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu 130 135 140 Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser 145 150 155 160 Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 165 170 175 Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser 180 185 190 Tyr Leu Asn Ala Ser 195 <210> SEQ ID NO 49 <211> LENGTH: 12 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 49 gtcgacgcca cc 12 <210> SEQ ID NO 50 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 50 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys 20 <210> SEQ ID NO 51 <211> LENGTH: 33 <212> TYPE: PRT <213> ORGANISM: Saccharomyces cerevisiae <400> SEQUENCE: 51 Arg Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile 1 5 10 15 Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu 20 25 30 Arg <210> SEQ ID NO 52 <211> LENGTH: 126 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro Leu Pro Ser 1 5 10 15 Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn Lys Val Ser 20 25 30 Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu Ile Tyr Gly 35 40 45 Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro Phe Glu Val 50 55 60 Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr Asn Lys Ser 65 70 75 80 Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val Gly Asp Thr 85 90 95 Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys Asn Asn Thr 100 105 110 Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile Ser 115 120 125 <210> SEQ ID NO 53 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 53 Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser 1 5 10 <210> SEQ ID NO 54 <211> LENGTH: 245 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 54 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala 65 70 75 80 Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp 85 90 95 Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr 100 105 110 Ala Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 130 135 140 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 145 150 155 160 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 165 170 175 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 180 185 190 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 195 200 205 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 210 215 220 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 225 230 235 240 Phe Ile Asn Thr Ser 245

<210> SEQ ID NO 55 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 55 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly 20 25 30 <210> SEQ ID NO 56 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr 1 5 10 15 Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly 20 25 30 Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala 35 40 45 His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val 50 55 60 His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr Ala 65 70 75 <210> SEQ ID NO 57 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 57 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 58 <211> LENGTH: 485 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 58 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Glu Ile Val Leu Thr Gln Ser Pro Ala Thr 20 25 30 Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser 35 40 45 Ser Ser Ile Ser Tyr Met His Trp Phe Gln Gln Arg Pro Gly Gln Ser 50 55 60 Pro Arg Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro 65 70 75 80 Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile 85 90 95 Ser Ser Leu Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Arg 100 105 110 Thr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 130 135 140 Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala Ser 145 150 155 160 Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp 165 170 175 Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 180 185 190 Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn Glu Val Phe Lys 195 200 205 Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr Met 210 215 220 Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala 225 230 235 240 Arg Gly Asp Tyr Gly Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 245 250 255 Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 260 265 270 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 275 280 285 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 290 295 300 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 305 310 315 320 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 325 330 335 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 340 345 350 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 355 360 365 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 370 375 380 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 385 390 395 400 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 405 410 415 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 420 425 430 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 435 440 445 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 450 455 460 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 465 470 475 480 Leu Ser Pro Gly Lys 485 <210> SEQ ID NO 59 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Ile Ser Tyr Met 20 25 30 His Trp Phe Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys His Gln Arg Thr Ser Tyr Pro Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 60 <211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 60 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Asn Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Ala Pro Gly Ser Gly Thr Thr Tyr Tyr Asn Glu Val Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Asp Tyr Gly Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 61 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 61 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 62 <211> LENGTH: 245 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 62 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala 65 70 75 80 Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp 85 90 95 Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr 100 105 110 Ala Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 130 135 140 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 145 150 155 160 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 165 170 175 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 180 185 190 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 195 200 205 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 210 215 220 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 225 230 235 240 Phe Ile Asn Thr Ser 245 <210> SEQ ID NO 63 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly 20 25 30 <210> SEQ ID NO 64 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 64 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 65 <211> LENGTH: 261 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 65 Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly 1 5 10 15 Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu 20 25 30 Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg 35 40 45 Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val 50 55 60 Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser 65 70 75 80 Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys 85 90 95 Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu 100 105 110 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 115 120 125 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 130 135 140 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 145 150 155 160 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 165 170 175 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 180 185 190 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 195 200 205 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 210 215 220 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 225 230 235 240 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 245 250 255 Gly Leu Leu Lys Leu 260 <210> SEQ ID NO 66 <211> LENGTH: 183 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 66 Met Glu Arg Val Gln Pro Leu Glu Glu Asn Val Gly Asn Ala Ala Arg 1 5 10 15 Pro Arg Phe Glu Arg Asn Lys Leu Leu Leu Val Ala Ser Val Ile Gln 20 25 30 Gly Leu Gly Leu Leu Leu Cys Phe Thr Tyr Ile Cys Leu His Phe Ser 35 40 45 Ala Leu Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val 50 55 60 Gln Phe Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln 65 70 75 80 Lys Glu Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn 85 90 95 Cys Asp Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu 100 105 110 Val Asn Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln 115 120 125 Leu Lys Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr 130 135 140 Tyr Lys Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu 145 150 155 160 Asp Asp Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn 165 170 175 Pro Gly Glu Phe Cys Val Leu 180

<210> SEQ ID NO 67 <211> LENGTH: 462 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 67 Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg 1 5 10 15 Leu Gly Ser Asp Ala His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val 20 25 30 Trp Phe Glu Ala Glu Phe Phe His His Ile Leu His Trp Thr Pro Ile 35 40 45 Pro Asn Gln Ser Glu Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr 50 55 60 Gly Ile Glu Ser Trp Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser 65 70 75 80 Tyr Asp Leu Thr Ala Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr 85 90 95 Arg Ala Arg Val Arg Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr 100 105 110 Val Thr Asn Thr Arg Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly 115 120 125 Ser Val Asn Leu Glu Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln 130 135 140 Leu Pro Arg Pro Lys Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile 145 150 155 160 Phe Ser His Phe Arg Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly 165 170 175 Asn Phe Thr Phe Thr His Lys Lys Val Lys His Glu Asn Phe Ser Leu 180 185 190 Leu Thr Ser Gly Glu Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser 195 200 205 Val Ala Ser Arg Ser Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile 210 215 220 Ser Leu Thr Arg Gln Tyr Phe Thr Val Thr Asn Asp Lys Thr His Thr 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 275 280 285 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 305 310 315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 325 330 335 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 355 360 365 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 420 425 430 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435 440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 68 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val Trp Phe Glu Ala Glu 1 5 10 15 Phe Phe His His Ile Leu His Trp Thr Pro Ile Pro Asn Gln Ser Glu 20 25 30 Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr Gly Ile Glu Ser Trp 35 40 45 Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser Tyr Asp Leu Thr Ala 50 55 60 Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr Arg Ala Arg Val Arg 65 70 75 80 Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr Val Thr Asn Thr Arg 85 90 95 Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly Ser Val Asn Leu Glu 100 105 110 Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln Leu Pro Arg Pro Lys 115 120 125 Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile Phe Ser His Phe Arg 130 135 140 Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly Asn Phe Thr Phe Thr 145 150 155 160 His Lys Lys Val Lys His Glu Asn Phe Ser Leu Leu Thr Ser Gly Glu 165 170 175 Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser Val Ala Ser Arg Ser 180 185 190 Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile Ser Leu Thr Arg Gln 195 200 205 Tyr Phe Thr Val Thr Asn 210 <210> SEQ ID NO 69 <211> LENGTH: 21 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 69 Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg 1 5 10 15 Leu Gly Ser Asp Ala 20 <210> SEQ ID NO 70 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 70 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 71 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 71 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro 65 70 75 80 Leu Pro Ser Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn 85 90 95

Lys Val Ser Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu 100 105 110 Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro 115 120 125 Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr 130 135 140 Asn Lys Ser Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val 145 150 155 160 Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys 165 170 175 Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile 180 185 190 Ser <210> SEQ ID NO 72 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val Gln Phe 1 5 10 15 Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln Lys Glu 20 25 30 Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn Cys Asp 35 40 45 Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu Val Asn 50 55 60 Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln Leu Lys 65 70 75 80 Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr Tyr Lys 85 90 95 Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu Asp Asp 100 105 110 Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn Pro Gly 115 120 125 Glu Phe Cys Val Leu 130 <210> SEQ ID NO 73 <211> LENGTH: 216 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 73 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His 65 70 75 80 Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala 85 90 95 Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn 100 105 110 Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala 115 120 125 Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe 130 135 140 Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu 145 150 155 160 Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln 165 170 175 Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val 180 185 190 Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe 195 200 205 Thr Ser Phe Gly Leu Leu Lys Leu 210 215 <210> SEQ ID NO 74 <400> SEQUENCE: 74 000 <210> SEQ ID NO 75 <400> SEQUENCE: 75 000 <210> SEQ ID NO 76 <211> LENGTH: 149 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 76 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 1 5 10 15 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 20 25 30 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 35 40 45 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 50 55 60 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 65 70 75 80 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 85 90 95 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 100 105 110 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 115 120 125 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 130 135 140 Gly Leu Leu Lys Leu 145 <210> SEQ ID NO 77 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 77 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His <210> SEQ ID NO 78 <211> LENGTH: 144 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 78 Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile 1 5 10 15 Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His 20 25 30 Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp 35 40 45 Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe 50 55 60 Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys 65 70 75 80 Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met 85 90 95 Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser 100 105 110 Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys 115 120 125 Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 130 135 140 <210> SEQ ID NO 79 <211> LENGTH: 144 <212> TYPE: PRT

<213> ORGANISM: Homo sapiens <400> SEQUENCE: 79 Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile 1 5 10 15 Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His 20 25 30 Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp 35 40 45 Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe 50 55 60 Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys 65 70 75 80 Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met 85 90 95 Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser 100 105 110 Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys 115 120 125 Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 130 135 140 <210> SEQ ID NO 80 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 80 Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro <210> SEQ ID NO 81 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 81 Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly 1 5 10 15 Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile 20 25 30 Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu 35 40 45 Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His 50 55 60 Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala 65 70 75 80 Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu 85 90 95 Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu 100 105 110 Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu 115 120 125 Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg 130 135 140 Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro 145 150 155 160 Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu 165 170 175 Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg 180 185 190 Pro <210> SEQ ID NO 82 <211> LENGTH: 387 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 82 atgactgaca ccctagatct agaaatggac ggaattatta cagagcagcg cctgctagaa 60 agacgcaggg cagcggccga gcaacagcgc atgaatcaag agctccaaga catggttaac 120 ttgcaccagt gcaaaagggg tatcttttgt ctggtaaagc aggccaaagt cacctacgac 180 agtaatacca ccggacaccg ccttagctac aagttgccaa ccaagcgtca gaaattggtg 240 gtcatggtgg gagaaaagcc cattaccata actcagcact cggtagaaac cgaaggctgc 300 attcactcac cttgtcaagg acctgaggat ctctgcaccc ttattaagac cctgtgcggt 360 ctcaaagatc ttattccctt taactaa 387 <210> SEQ ID NO 83 <211> LENGTH: 399 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 83 atgaaattta ctgtgacttt tctgctgatt atttgcaccc tatctgcgtt ttgttccccg 60 acctccaagc ctcaaagaca tatatcatgc agattcactc gtatatggaa tattccaagt 120 tgctacaatg aaaaaagcga tctttccgaa gcctggttat atgcaatcat ctctgttatg 180 gtgttctgca gtaccatctt agccctagct atatatccct accttgacat tggctggaac 240 gcaatagatg ccatgaacca cccaactttc cccgcgcccg ctatgcttcc actgcaacaa 300 gttgttgccg gcggctttgt cccagccaat cagcctcgcc caccttctcc cacccccact 360 gaaatcagct actttaatct aacaggagga gatgactga 399 <210> SEQ ID NO 84 <211> LENGTH: 192 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 84 atgattcctc gagtttttat attactgacc cttgttgcgc tttttttgtg cgtgctccac 60 attggctgcg gtttctcaca tcgaagtaga ctgcattcca gccttcacag tctatttgct 120 ttacggattt gtcaccctca cgctcatctg cagcctcatc actgtggtca tcgcctttat 180 ccagtgcatt ga 192 <210> SEQ ID NO 85 <211> LENGTH: 282 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 85 atgaccaaca caaccaacgc ggccgccgct accggactta catctaccac aaatacaccc 60 caagtttctg cctttgtcaa taactgggat aacttgggca tgtggtggtt ctccatagcg 120 cttatgtttg tatgccttat tattatgtgg ctcatctgct gcctaaagcg caaacgcgcc 180 cgaccaccca tctatagtcc catcattgtg ctacacccaa acaatgatgg aatccataga 240 ttggacggac tgaaacacat gttcttttct cttacagtat ga 282 <210> SEQ ID NO 86 <211> LENGTH: 483 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 86 atgattaggt acataatcct aggtttactc acccttgcgt cagcccacgg taccacccaa 60 aaggtggatt ttaaggagcc agcctgtaat gttacattcg cagctgaagc taatgagtgc 120 accactctta taaaatgcac cacagaacat gaaaagctgc ttattcgcca caaaaacaaa 180 attggcaagt atgctgttta tgctatttgg cagccaggtg acactacaga gtataatgtt 240 acagttttcc agggtaaaag tcataaaact tttatgtata cttttccatt ttatgaaatg 300 tgcgacatta ccatgtacat gagcaaacag tataagttgt ggcccccaca aaattgtgtg 360 gaaaacactg gcactttctg ctgcactgct atgctaatta cagtgctcgc tttggtctgt 420 accctactct atattaaata caaaagcaga cgcagcttta ttgaggaaaa gaaaatgcct 480 taa 483

<210> SEQ ID NO 87 <211> LENGTH: 192 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 87 atgaacaatt caagcaactc tacgggctat tctaattcag gtttctctag aatcggggtt 60 ggggttattc tctgtcttgt gattctcttt attcttatac taacgcttct ctgcctaagg 120 ctcgccgcct gctgtgtgca catttgcatt tattgtcagc tttttaaacg ctggggtcgc 180 cacccaagat ga 192 <210> SEQ ID NO 88 <211> LENGTH: 324 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 88 atgttaagtg gagaggcaga gcaactgcgc ctgaaacacc tggtccactg tcgccgccac 60 aagtgctttg cccgcgactc cggtgagttt tgctactttg aattgcccga ggatcatatc 120 gagggcccgg cgcacggcgt ccggcttacc gcccagggag agcttgcccg tagcctgatt 180 cgggagttta cccagcgccc cctgctagtt gagcgggaca ggggaccctg tgttctcact 240 gtgatttgca actgtcctaa ccctggatta catcaagatc tttgttgcca tctctgtgct 300 gagtataata aatacagaaa ttaa 324 <210> SEQ ID NO 89 <211> LENGTH: 379 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 89 caccctagat ctagaaatgg acggaattat tacagagcag cgcctgctag aaagacgcag 60 ggcagcggcc gagcaacagc gcatgaatca agagctccaa gacatggtta acttgcacca 120 gtgcaaaagg ggtatctttt gtctggtaaa gcaggccaaa gtcacctacg acagtaatac 180 caccggacac cgccttagct acaagttgcc aaccaagcgt cagaaattgg tggtcatggt 240 gggagaaaag cccattacca taactcagca ctcggtagaa accgaaggct gcattcactc 300 accttgtcaa ggacctgagg atctctgcac ccttattaag accctgtgcg gtctcaaaga 360 tcttattccc tttaactaa 379 <210> SEQ ID NO 90 <211> LENGTH: 755 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 90 agacgcccag gccgaagttc agatgactaa ctcaggggcg cagcttgcgg gcggctttcg 60 tcacagggtg cggtcgcccg ggcagggtat aactcacctg acaatcagag ggcgaggtat 120 tcagctcaac gacgagtcgg tgagctcctc gcttggtctc cgtccggacg ggacatttca 180 gatcggcggc gccggccgct cttcattcac gcctcgtcag gcaatcctaa ctctgcagac 240 ctcgtcctct gagccgcgct ctggaggcat tggaactctg caatttattg aggagtttgt 300 gccatcggtc tactttaacc ccttctcggg acctcccggc cactatccgg atcaatttat 360 tcctaacttt gacgcggtaa aggactcggc ggacggctac gactgaatgt taagtggaga 420 ggcagagcaa ctgcgcctga aacacctggt ccactgtcgc cgccacaagt gctttgcccg 480 cgactccggt gagttttgct actttgaatt gcccgaggat catatcgagg gcccggcgca 540 cggcgtccgg cttaccgccc agggagagct tgcccgtagc ctgattcggg agtttaccca 600 gcgccccctg ctagttgagc gggacagggg accctgtgtt ctcactgtga tttgcaactg 660 tcctaaccct ggattacatc aagatcctct agttaatgtc aggtcgccta agtcgattaa 720 ctagagtacc cggggatctt attcccttta actaa 755 <210> SEQ ID NO 91 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 91 gatcttattc cctttaacta a 21 <210> SEQ ID NO 92 <211> LENGTH: 279 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 92 atgttaagtg gagaggcaga gcaactgcgc ctgaaacacc tggtccactg tcgccgccac 60 aagtgctttg cccgcgactc cggtgagttt tgctactttg aattgcccga ggatcatatc 120 gagggcccgg cgcacggcgt ccggcttacc gcccagggag agcttgcccg tagcctgatt 180 cgggagttta cccagcgccc cctgctagtt gagcgggaca ggggaccctg tgttctcact 240 gtgatttgca actgtcctaa ccctggatta catcaagat 279 <210> SEQ ID NO 93 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 93 agacgcccag gccgaagttc agatgacta 29 <210> SEQ ID NO 94 <211> LENGTH: 33225 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 94 ttttggattg aagccaatat gataatgagg gggtggagtt tgtgacgtgg cgcggggcgt 60 gggaacgggg cgggtgacgt agtagtgtgg cggaagtgtg atgttgcaag tgtggcggaa 120 cacatgtaag cgacggatgt ggcaaaagtg acgtttttgg tgtgcgccgg tgttttgggc 180 gtaaccgagt aagatttggc cattttcgcg ggaaaactga ataagaggaa gtgaaatctg 240 aataattttg tgttactcat agcgcgtaat atttgtctag ggccgcgggg actttgaccg 300 tttacgtgga gactcgccca ggtgtttttc tcaggtgttt tccgcgttcc gggtcaaagt 360 tggcgtttta ttattatagt cagctgacgt gtagtgtatt tatacccggt gagttcctca 420 agaggccact cttgagtgcc agcgagtaga gttttctcct ccgagccgct ccgacaccgg 480 gactgaaaat gagacatatt atctgccacg gaggtgttat taccgaagaa atggccgcca 540 gtcttttgga ccagctgatc gaagaggtac tggctgataa tcttccacct cctagccatt 600 ttgaaccacc tacccttcac gaactgtatg atttagacgt gacggccccc gaagatccca 660 acgaggaggc ggtttcgcag atttttcccg actctgtaat gttggcggtg caggaaggga 720 ttgacttact cacttttccg ccggcgcccg gttctccgga gccgcctcac ctttcccggc 780 agcccgagca gccggagcag agagccttgg gtccggtttc tatgccaaac cttgtaccgg 840 aggtgatcga tcttacctgc cacgaggctg gctttccacc cagtgacgac gaggatgaag 900 agggtgagga gtttgtgtta gattatgtgg agcaccccgg gcacggttgc aggtcttgtc 960 attatcaccg gaggaatacg ggggacccag atattatgtg ttcgctttgc tatatgagga 1020 cctgtggcat gtttgtctac agtaagtgaa aattatgggc agtgggtgat agagtggtgg 1080 gtttggtgtg gtaatttttt ttttaatttt tacagttttg tggtttaaag aattttgtat 1140 tgtgattttt ttaaaaggtc ctgtgtctga acctgagcct gagcccgagc cagaaccgga 1200 gcctgcaaga cctacccgcc gtcctaaaat ggcgcctgct atcctgagac gcccgacatc 1260 acctgtgtct agagaatgca atagtagtac ggatagctgt gactccggtc cttctaacac 1320 acctcctgag atacacccgg tggtcccgct gtgccccatt aaaccagttg ccgtgagagt 1380 tggtgggcgt cgccaggctg tggaatgtat cgaggacttg cttaacgagc ctgggcaacc 1440 tttggacttg agctgtaaac gccccaggcc ataaggtgta aacctgtgat tgcgtgtgtg 1500 gttaacgcct ttgtttgctg aatgagttga tgtaagttta ataaagggtg agataatgtt 1560 taacttgcat ggcgtgttaa atggggcggg gcttaaaggg tatataatgc gccgtgggct 1620 aatcttggtt acatctgacc tcgtcgacgc ttgggagtgt ttggaagatt tttctgctgt 1680 gcgtaacttg ctggaacaga gctctaacag tacctcttgg ttttggaggt ttctgtgggg 1740 ctcatcccag gcaaagttag tctgcagaat taaggaggat tacaagtggg aatttgaaga 1800 gcttttgaaa tcctgtggtg agctgtttga ttctttgaac tcgagtcacc aggcgctttt 1860 ccaagagaag gtcatcaaga ctttggattt ttccacaccg gggcgcgctg cggctgctgt 1920 tgcttttttg agttttataa aggataaatg gagcgaagaa acccatctga gcggggggta 1980 cctgctggat tttctggcca tgcatctgtg gagagcggtt gtgagacaca agaatcgcct 2040 gctactgttg tcttccgtcc gcccggcgat aataccgacg gaggagcagc agcagcagca 2100 ggaggaagcc aggcggcggc ggcaggagca gagcccatgg aacccgagag ccggcctgga 2160 ccctcgggaa tgaatgttgt acaggtggct gaactgtatc cagaactgag acgcattttg 2220 acaattacag aggatgggca ggggctaaag ggggtaaaga gggagcgggg ggcttgtgag 2280 gctacagagg aggctaggaa tctagctttt agcttaatga ccagacaccg tcctgagtgt 2340 attacttttc aacagatcaa ggataattgc gctaatgagc ttgatctgct ggcgcagaag 2400 tattccatag agcagctgac cacttactgg ctgcagccag gggatgattt tgaggaggct 2460

attagggtat atgcaaaggt ggcacttagg ccagattgca agtacaagat cagcaaactt 2520 gtaaatatca ggaattgttg ctacatttct gggaacgggg ccgaggtgga gatagatacg 2580 gaggataggg tggcctttag atgtagcatg ataaatatgt ggccgggggt gcttggcatg 2640 gacggggtgg ttattatgaa tgtaaggttt actggcccca attttagcgg tacggttttc 2700 ctggccaata ccaaccttat cctacacggt gtaagcttct atgggtttaa caatacctgt 2760 gtggaagcct ggaccgatgt aagggttcgg ggctgtgcct tttactgctg ctggaagggg 2820 gtggtgtgtc gccccaaaag cagggcttca attaagaaat gcctctttga aaggtgtacc 2880 ttgggtatcc tgtctgaggg taactccagg gtgcgccaca atgtggcctc cgactgtggt 2940 tgcttcatgc tagtgaaaag cgtggctgtg attaagcata acatggtatg tggcaactgc 3000 gaggacaggg cctctcagat gctgacctgc tcggacggca actgtcacct gctgaagacc 3060 attcacgtag ccagccactc tcgcaaggcc tggccagtgt ttgagcataa catactgacc 3120 cgctgttcct tgcatttggg taacaggagg ggggtgttcc taccttacca atgcaatttg 3180 agtcacacta agatattgct tgagcccgag agcatgtcca aggtgaacct gaacggggtg 3240 tttgacatga ccatgaagat ctggaaggtg ctgaggtacg atgagacccg caccaggtgc 3300 agaccctgcg agtgtggcgg taaacatatt aggaaccagc ctgtgatgct ggatgtgacc 3360 gaggagctga ggcccgatca cttggtgctg gcctgcaccc gcgctgagtt tggctctagc 3420 gatgaagata cagattgagg tactgaaatg tgtgggcgtg gcttaagggt gggaaagaat 3480 atataaggtg ggggtcttat gtagttttgt atctgttttg cagcagccgc cgccgccatg 3540 agcaccaact cgtttgatgg aagcattgtg agctcatatt tgacaacgcg catgccccca 3600 tgggccgggg tgcgtcagaa tgtgatgggc tccagcattg atggtcgccc cgtcctgccc 3660 gcaaactcta ctaccttgac ctacgagacc gtgtctggaa cgccgttgga gactgcagcc 3720 tccgccgccg cttcagccgc tgcagccacc gcccgcggga ttgtgactga ctttgctttc 3780 ctgagcccgc ttgcaagcag tgcagcttcc cgttcatccg cccgcgatga caagttgacg 3840 gctcttttgg cacaattgga ttctttgacc cgggaactta atgtcgtttc tcagcagctg 3900 ttggatctgc gccagcaggt ttctgccctg aaggcttcct cccctcccaa tgcggtttaa 3960 aacataaata aaaaaccaga ctctgtttgg atttggatca agcaagtgtc ttgctgtctt 4020 tatttagggg ttttgcgcgc gcggtaggcc cgggaccagc ggtctcggtc gttgagggtc 4080 ctgtgtattt tttccaggac gtggtaaagg tgactctgga tgttcagata catgggcata 4140 agcccgtctc tggggtggag gtagcaccac tgcagagctt catgctgcgg ggtggtgttg 4200 tagatgatcc agtcgtagca ggagcgctgg gcgtggtgcc taaaaatgtc tttcagtagc 4260 aagctgattg ccaggggcag gcccttggtg taagtgttta caaagcggtt aagctgggat 4320 gggtgcatac gtggggatat gagatgcatc ttggactgta tttttaggtt ggctatgttc 4380 ccagccatat ccctccgggg attcatgttg tgcagaacca ccagcacagt gtatccggtg 4440 cacttgggaa atttgtcatg tagcttagaa ggaaatgcgt ggaagaactt ggagacgccc 4500 ttgtgacctc caagattttc catgcattcg tccataatga tggcaatggg cccacgggcg 4560 gcggcctggg cgaagatatt tctgggatca ctaacgtcat agttgtgttc caggatgaga 4620 tcgtcatagg ccatttttac aaagcgcggg cggagggtgc cagactgcgg tataatggtt 4680 ccatccggcc caggggcgta gttaccctca cagatttgca tttcccacgc tttgagttca 4740 gatgggggga tcatgtctac ctgcggggcg atgaagaaaa cggtttccgg ggtaggggag 4800 atcagctggg aagaaagcag gttcctgagc agctgcgact taccgcagcc ggtgggcccg 4860 taaatcacac ctattaccgg ctgcaactgg tagttaagag agctgcagct gccgtcatcc 4920 ctgagcaggg gggccacttc gttaagcatg tccctgactc gcatgttttc cctgaccaaa 4980 tccgccagaa ggcgctcgcc gcccagcgat agcagttctt gcaaggaagc aaagtttttc 5040 aacggtttga gaccgtccgc cgtaggcatg cttttgagcg tttgaccaag cagttccagg 5100 cggtcccaca gctcggtcac ctgctctacg gcatctcgat ccagcatatc tcctcgtttc 5160 gcgggttggg gcggctttcg ctgtacggca gtagtcggtg ctcgtccaga cgggccaggg 5220 tcatgtcttt ccacgggcgc agggtcctcg tcagcgtagt ctgggtcacg gtgaaggggt 5280 gcgctccggg ctgcgcgctg gccagggtgc gcttgaggct ggtcctgctg gtgctgaagc 5340 gctgccggtc ttcgccctgc gcgtcggcca ggtagcattt gaccatggtg tcatagtcca 5400 gcccctccgc ggcgtggccc ttggcgcgca gcttgccctt ggaggaggcg ccgcacgagg 5460 ggcagtgcag acttttgagg gcgtagagct tgggcgcgag aaataccgat tccggggagt 5520 aggcatccgc gccgcaggcc ccgcagacgg tctcgcattc cacgagccag gtgagctctg 5580 gccgttcggg gtcaaaaacc aggtttcccc catgcttttt gatgcgtttc ttacctctgg 5640 tttccatgag ccggtgtcca cgctcggtga cgaaaaggct gtccgtgtcc ccgtatacag 5700 acttgagagg cctgtcctcg agcggtgttc cgcggtcctc ctcgtataga aactcggacc 5760 actctgagac aaaggctcgc gtccaggcca gcacgaagga ggctaagtgg gaggggtagc 5820 ggtcgttgtc cactaggggg tccactcgct ccagggtgtg aagacacatg tcgccctctt 5880 cggcatcaag gaaggtgatt ggtttgtagg tgtaggccac gtgaccgggt gttcctgaag 5940 gggggctata aaagggggtg ggggcgcgtt cgtcctcact ctcttccgca tcgctgtctg 6000 cgagggccag ctgttggggt gagtactccc tctgaaaagc gggcatgact tctgcgctaa 6060 gattgtcagt ttccaaaaac gaggaggatt tgatattcac ctggcccgcg gtgatgcctt 6120 tgagggtggc cgcatccatc tggtcagaaa agacaatctt tttgttgtca agcttggtgg 6180 caaacgaccc gtagagggcg ttggacagca acttggcgat ggagcgcagg gtttggtttt 6240 tgtcgcgatc ggcgcgctcc ttggccgcga tgtttagctg cacgtattcg cgcgcaacgc 6300 accgccattc gggaaagacg gtggtgcgct cgtcgggcac caggtgcacg cgccaaccgc 6360 ggttgtgcag ggtgacaagg tcaacgctgg tggctacctc tccgcgtagg cgctcgttgg 6420 tccagcagag gcggccgccc ttgcgcgagc agaatggcgg tagggggtct agctgcgtct 6480 cgtccggggg gtctgcgtcc acggtaaaga ccccgggcag caggcgcgcg tcgaagtagt 6540 ctatcttgca tccttgcaag tctagcgcct gctgccatgc gcgggcggca agcgcgcgct 6600 cgtatgggtt gagtggggga ccccatggca tggggtgggt gagcgcggag gcgtacatgc 6660 cgcaaatgtc gtaaacgtag aggggctctc tgagtattcc aagatatgta gggtagcatc 6720 ttccaccgcg gatgctggcg cgcacgtaat cgtatagttc gtgcgaggga gcgaggaggt 6780 cgggaccgag gttgctacgg gcgggctgct ctgctcggaa gactatctgc ctgaagatgg 6840 catgtgagtt ggatgatatg gttggacgct ggaagacgtt gaagctggcg tctgtgagac 6900 ctaccgcgtc acgcacgaag gaggcgtagg agtcgcgcag cttgttgacc agctcggcgg 6960 tgacctgcac gtctagggcg cagtagtcca gggtttcctt gatgatgtca tacttatcct 7020 gtcccttttt tttccacagc tcgcggttga ggacaaactc ttcgcggtct ttccagtact 7080 cttggatcgg aaacccgtcg gcctccgaac ggtaagagcc tagcatgtag aactggttga 7140 cggcctggta ggcgcagcat cccttttcta cgggtagcgc gtatgcctgc gcggccttcc 7200 ggagcgaggt gtgggtgagc gcaaaggtgt ccctgaccat gactttgagg tactggtatt 7260 tgaagtcagt gtcgtcgcat ccgccctgct cccagagcaa aaagtccgtg cgctttttgg 7320 aacgcggatt tggcagggcg aaggtgacat cgttgaagag tatctttccc gcgcgaggca 7380 taaagttgcg tgtgatgcgg aagggtcccg gcacctcgga acggttgtta attacctggg 7440 cggcgagcac gatctcgtca aagccgttga tgttgtggcc cacaatgtaa agttccaaga 7500 agcgcgggat gcccttgatg gaaggcaatt ttttaagttc ctcgtaggtg agctcttcag 7560 gggagctgag cccgtgctct gaaagggccc agtctgcaag atgagggttg gaagcgacga 7620 atgagctcca caggtcacgg gccattagca tttgcaggtg gtcgcgaaag gtcctaaact 7680 ggcgacctat ggccattttt tctggggtga tgcagtagaa ggtaagcggg tcttgttccc 7740 agcggtccca tccaaggttc gcggctaggt ctcgcgcggc agtcactaga ggctcatctc 7800 cgccgaactt catgaccagc atgaagggca cgagctgctt cccaaaggcc cccatccaag 7860 tataggtctc tacatcgtag gtgacaaaga gacgctcggt gcgaggatgc gagccgatcg 7920 ggaagaactg gatctcccgc caccaattgg aggagtggct attgatgtgg tgaaagtaga 7980 agtccctgcg acgggccgaa cactcgtgct ggcttttgta aaaacgtgcg cagtactggc 8040 agcggtgcac gggctgtaca tcctgcacga ggttgacctg acgaccgcgc acaaggaagc 8100 agagtgggaa tttgagcccc tcgcctggcg ggtttggctg gtggtcttct acttcggctg 8160 cttgtccttg accgtctggc tgctcgaggg gagttacggt ggatcggacc accacgccgc 8220 gcgagcccaa agtccagatg tccgcgcgcg gcggtcggag cttgatgaca acatcgcgca 8280 gatgggagct gtccatggtc tggagctccc gcggcgtcag gtcaggcggg agctcctgca 8340 ggtttacctc gcatagacgg gtcagggcgc gggctagatc caggtgatac ctaatttcca 8400 ggggctggtt ggtggcggcg tcgatggctt gcaagaggcc gcatccccgc ggcgcgacta 8460 cggtaccgcg cggcgggcgg tgggccgcgg gggtgtcctt ggatgatgca tctaaaagcg 8520 gtgacgcggg cgagcccccg gaggtagggg gggctccgga cccgccggga gagggggcag 8580 gggcacgtcg gcgccgcgcg cgggcaggag ctggtgctgc gcgcgtaggt tgctggcgaa 8640 cgcgacgacg cggcggttga tctcctgaat ctggcgcctc tgcgtgaaga cgacgggccc 8700 ggtgagcttg aacctgaaag agagttcgac agaatcaatt tcggtgtcgt tgacggcggc 8760 ctggcgcaaa atctcctgca cgtctcctga gttgtcttga taggcgatct cggccatgaa 8820 ctgctcgatc tcttcctcct ggagatctcc gcgtccggct cgctccacgg tggcggcgag 8880 gtcgttggaa atgcgggcca tgagctgcga gaaggcgttg aggcctccct cgttccagac 8940 gcggctgtag accacgcccc cttcggcatc gcgggcgcgc atgaccacct gcgcgagatt 9000 gagctccacg tgccgggcga agacggcgta gtttcgcagg cgctgaaaga ggtagttgag 9060 ggtggtggcg gtgtgttctg ccacgaagaa gtacataacc cagcgtcgca acgtggattc 9120 gttgatatcc cccaaggcct caaggcgctc catggcctcg tagaagtcca cggcgaagtt 9180 gaaaaactgg gagttgcgcg ccgacacggt taactcctcc tccagaagac ggatgagctc 9240 ggcgacagtg tcgcgcacct cgcgctcaaa ggctacaggg gcctcttctt cttcttcaat 9300 ctcctcttcc ataagggcct ccccttcttc ttcttctggc ggcggtgggg gaggggggac 9360 acggcggcga cgacggcgca ccgggaggcg gtcgacaaag cgctcgatca tctccccgcg 9420 gcgacggcgc atggtctcgg tgacggcgcg gccgttctcg cgggggcgca gttggaagac 9480 gccgcccgtc atgtcccggt tatgggttgg cggggggctg ccatgcggca gggatacggc 9540 gctaacgatg catctcaaca attgttgtgt aggtactccg ccgccgaggg acctgagcga 9600 gtccgcatcg accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca 9660 aggtaggctg agcaccgtgg cgggcggcag cgggcggcgg tcggggttgt ttctggcgga 9720 ggtgctgctg atgatgtaat taaagtaggc ggtcttgaga cggcggatgg tcgacagaag 9780 caccatgtcc ttgggtccgg cctgctgaat gcgcaggcgg tcggccatgc cccaggcttc 9840 gttttgacat cggcgcaggt ctttgtagta gtcttgcatg agcctttcta ccggcacttc 9900 ttcttctcct tcctcttgtc ctgcatctct tgcatctatc gctgcggcgg cggcggagtt 9960

tggccgtagg tggcgccctc ttcctcccat gcgtgtgacc ccgaagcccc tcatcggctg 10020 aagcagggct aggtcggcga caacgcgctc ggctaatatg gcctgctgca cctgcgtgag 10080 ggtagactgg aagtcatcca tgtccacaaa gcggtggtat gcgcccgtgt tgatggtgta 10140 agtgcagttg gccataacgg accagttaac ggtctggtga cccggctgcg agagctcggt 10200 gtacctgaga cgcgagtaag ccctcgagtc aaatacgtag tcgttgcaag tccgcaccag 10260 gtactggtat cccaccaaaa agtgcggcgg cggctggcgg tagaggggcc agcgtagggt 10320 ggccggggct ccgggggcga gatcttccaa cataaggcga tgatatccgt agatgtacct 10380 ggacatccag gtgatgccgg cggcggtggt ggaggcgcgc ggaaagtcgc ggacgcggtt 10440 ccagatgttg cgcagcggca aaaagtgctc catggtcggg acgctctggc cggtcaggcg 10500 cgcgcaatcg ttgacgctct agcgtgcaaa aggagagcct gtaagcgggc actcttccgt 10560 ggtctggtgg ataaattcgc aagggtatca tggcggacga ccggggttcg agccccgtat 10620 ccggccgtcc gccgtgatcc atgcggttac cgcccgcgtg tcgaacccag gtgtgcgacg 10680 tcagacaacg ggggagtgct ccttttggct tccttccagg cgcggcggct gctgcgctag 10740 cttttttggc cactggccgc gcgcagcgta agcggttagg ctggaaagcg aaagcattaa 10800 gtggctcgct ccctgtagcc ggagggttat tttccaaggg ttgagtcgcg ggacccccgg 10860 ttcgagtctc ggaccggccg gactgcggcg aacgggggtt tgcctccccg tcatgcaaga 10920 ccccgcttgc aaattcctcc ggaaacaggg acgagcccct tttttgcttt tcccagatgc 10980 atccggtgct gcggcagatg cgcccccctc ctcagcagcg gcaagagcaa gagcagcggc 11040 agacatgcag ggcaccctcc cctcctccta ccgcgtcagg aggggcgaca tccgcggttg 11100 acgcggcagc agatggtgat tacgaacccc cgcggcgccg ggcccggcac tacctggact 11160 tggaggaggg cgagggcctg gcgcggctag gagcgccctc tcctgagcgg cacccaaggg 11220 tgcagctgaa gcgtgatacg cgtgaggcgt acgtgccgcg gcagaacctg tttcgcgacc 11280 gcgagggaga ggagcccgag gagatgcggg atcgaaagtt ccacgcaggg cgcgagctgc 11340 ggcatggcct gaatcgcgag cggttgctgc gcgaggagga ctttgagccc gacgcgcgaa 11400 ccgggattag tcccgcgcgc gcacacgtgg cggccgccga cctggtaacc gcatacgagc 11460 agacggtgaa ccaggagatt aactttcaaa aaagctttaa caaccacgtg cgtacgcttg 11520 tggcgcgcga ggaggtggct ataggactga tgcatctgtg ggactttgta agcgcgctgg 11580 agcaaaaccc aaatagcaag ccgctcatgg cgcagctgtt ccttatagtg cagcacagca 11640 gggacaacga ggcattcagg gatgcgctgc taaacatagt agagcccgag ggccgctggc 11700 tgctcgattt gataaacatc ctgcagagca tagtggtgca ggagcgcagc ttgagcctgg 11760 ctgacaaggt ggccgccatc aactattcca tgcttagcct gggcaagttt tacgcccgca 11820 agatatacca taccccttac gttcccatag acaaggaggt aaagatcgag gggttctaca 11880 tgcgcatggc gctgaaggtg cttaccttga gcgacgacct gggcgtttat cgcaacgagc 11940 gcatccacaa ggccgtgagc gtgagccggc ggcgcgagct cagcgaccgc gagctgatgc 12000 acagcctgca aagggccctg gctggcacgg gcagcggcga tagagaggcc gagtcctact 12060 ttgacgcggg cgctgacctg cgctgggccc caagccgacg cgccctggag gcagctgggg 12120 ccggacctgg gctggcggtg gcacccgcgc gcgctggcaa cgtcggcggc gtggaggaat 12180 atgacgagga cgatgagtac gagccagagg acggcgagta ctaagcggtg atgtttctga 12240 tcagatgatg caagacgcaa cggacccggc ggtgcgggcg gcgctgcaga gccagccgtc 12300 cggccttaac tccacggacg actggcgcca ggtcatggac cgcatcatgt cgctgactgc 12360 gcgcaatcct gacgcgttcc ggcagcagcc gcaggccaac cggctctccg caattctgga 12420 agcggtggtc ccggcgcgcg caaaccccac gcacgagaag gtgctggcga tcgtaaacgc 12480 gctggccgaa aacagggcca tccggcccga cgaggccggc ctggtctacg acgcgctgct 12540 tcagcgcgtg gctcgttaca acagcggcaa cgtgcagacc aacctggacc ggctggtggg 12600 ggatgtgcgc gaggccgtgg cgcagcgtga gcgcgcgcag cagcagggca acctgggctc 12660 catggttgca ctaaacgcct tcctgagtac acagcccgcc aacgtgccgc ggggacagga 12720 ggactacacc aactttgtga gcgcactgcg gctaatggtg actgagacac cgcaaagtga 12780 ggtgtaccag tctgggccag actatttttt ccagaccagt agacaaggcc tgcagaccgt 12840 aaacctgagc caggctttca aaaacttgca ggggctgtgg ggggtgcggg ctcccacagg 12900 cgaccgcgcg accgtgtcta gcttgctgac gcccaactcg cgcctgttgc tgctgctaat 12960 agcgcccttc acggacagtg gcagcgtgtc ccgggacaca tacctaggtc acttgctgac 13020 actgtaccgc gaggccatag gtcaggcgca tgtggacgag catactttcc aggagattac 13080 aagtgtcagc cgcgcgctgg ggcaggagga cacgggcagc ctggaggcaa ccctaaacta 13140 cctgctgacc aaccggcggc agaagatccc ctcgttgcac agtttaaaca gcgaggagga 13200 gcgcattttg cgctacgtgc agcagagcgt gagccttaac ctgatgcgcg acggggtaac 13260 gcccagcgtg gcgctggaca tgaccgcgcg caacatggaa ccgggcatgt atgcctcaaa 13320 ccggccgttt atcaaccgcc taatggacta cttgcatcgc gcggccgccg tgaaccccga 13380 gtatttcacc aatgccatct tgaacccgca ctggctaccg ccccctggtt tctacaccgg 13440 gggattcgag gtgcccgagg gtaacgatgg attcctctgg gacgacatag acgacagcgt 13500 gttttccccg caaccgcaga ccctgctaga gttgcaacag cgcgagcagg cagaggcggc 13560 gctgcgaaag gaaagcttcc gcaggccaag cagcttgtcc gatctaggcg ctgcggcccc 13620 gcggtcagat gctagtagcc catttccaag cttgataggg tctcttacca gcactcgcac 13680 cacccgcccg cgcctgctgg gcgaggagga gtacctaaac aactcgctgc tgcagccgca 13740 gcgcgaaaaa aacctgcctc cggcatttcc caacaacggg atagagagcc tagtggacaa 13800 gatgagtaga tggaagacgt acgcgcagga gcacagggac gtgccaggcc cgcgcccgcc 13860 cacccgtcgt caaaggcacg accgtcagcg gggtctggtg tgggaggacg atgactcggc 13920 agacgacagc agcgtcctgg atttgggagg gagtggcaac ccgtttgcgc accttcgccc 13980 caggctgggg agaatgtttt aaaaaaaaaa aagcatgatg caaaataaaa aactcaccaa 14040 ggccatggca ccgagcgttg gttttcttgt attcccctta gtatgcggcg cgcggcgatg 14100 tatgaggaag gtcctcctcc ctcctacgag agtgtggtga gcgcggcgcc agtggcggcg 14160 gcgctgggtt ctcccttcga tgctcccctg gacccgccgt ttgtgcctcc gcggtacctg 14220 cggcctaccg gggggagaaa cagcatccgt tactctgagt tggcacccct attcgacacc 14280 acccgtgtgt acctggtgga caacaagtca acggatgtgg catccctgaa ctaccagaac 14340 gaccacagca actttctgac cacggtcatt caaaacaatg actacagccc gggggaggca 14400 agcacacaga ccatcaatct tgacgaccgg tcgcactggg gcggcgacct gaaaaccatc 14460 ctgcatacca acatgccaaa tgtgaacgag ttcatgttta ccaataagtt taaggcgcgg 14520 gtgatggtgt cgcgcttgcc tactaaggac aatcaggtgg agctgaaata cgagtgggtg 14580 gagttcacgc tgcccgaggg caactactcc gagaccatga ccatagacct tatgaacaac 14640 gcgatcgtgg agcactactt gaaagtgggc agacagaacg gggttctgga aagcgacatc 14700 ggggtaaagt ttgacacccg caacttcaga ctggggtttg accccgtcac tggtcttgtc 14760 atgcctgggg tatatacaaa cgaagccttc catccagaca tcattttgct gccaggatgc 14820 ggggtggact tcacccacag ccgcctgagc aacttgttgg gcatccgcaa gcggcaaccc 14880 ttccaggagg gctttaggat cacctacgat gatctggagg gtggtaacat tcccgcactg 14940 ttggatgtgg acgcctacca ggcgagcttg aaagatgaca ccgaacaggg cgggggtggc 15000 gcaggcggca gcaacagcag tggcagcggc gcggaagaga actccaacgc ggcagccgcg 15060 gcaatgcagc cggtggagga catgaacgat catgccattc gcggcgacac ctttgccaca 15120 cgggctgagg agaagcgcgc tgaggccgaa gcagcggccg aagctgccgc ccccgctgcg 15180 caacccgagg tcgagaagcc tcagaagaaa ccggtgatca aacccctgac agaggacagc 15240 aagaaacgca gttacaacct aataagcaat gacagcacct tcacccagta ccgcagctgg 15300 taccttgcat acaactacgg cgaccctcag accggaatcc gctcatggac cctgctttgc 15360 actcctgacg taacctgcgg ctcggagcag gtctactggt cgttgccaga catgatgcaa 15420 gaccccgtga ccttccgctc cacgcgccag atcagcaact ttccggtggt gggcgccgag 15480 ctgttgcccg tgcactccaa gagcttctac aacgaccagg ccgtctactc ccaactcatc 15540 cgccagttta cctctctgac ccacgtgttc aatcgctttc ccgagaacca gattttggcg 15600 cgcccgccag cccccaccat caccaccgtc agtgaaaacg ttcctgctct cacagatcac 15660 gggacgctac cgctgcgcaa cagcatcgga ggagtccagc gagtgaccat tactgacgcc 15720 agacgccgca cctgccccta cgtttacaag gccctgggca tagtctcgcc gcgcgtccta 15780 tcgagccgca ctttttgagc aagcatgtcc atccttatat cgcccagcaa taacacaggc 15840 tggggcctgc gcttcccaag caagatgttt ggcggggcca agaagcgctc cgaccaacac 15900 ccagtgcgcg tgcgcgggca ctaccgcgcg ccctggggcg cgcacaaacg cggccgcact 15960 gggcgcacca ccgtcgatga cgccatcgac gcggtggtgg aggaggcgcg caactacacg 16020 cccacgccgc caccagtgtc cacagtggac gcggccattc agaccgtggt gcgcggagcc 16080 cggcgctatg ctaaaatgaa gagacggcgg aggcgcgtag cacgtcgcca ccgccgccga 16140 cccggcactg ccgcccaacg cgcggcggcg gccctgctta accgcgcacg tcgcaccggc 16200 cgacgggcgg ccatgcgggc cgctcgaagg ctggccgcgg gtattgtcac tgtgcccccc 16260 aggtccaggc gacgagcggc cgccgcagca gccgcggcca ttagtgctat gactcagggt 16320 cgcaggggca acgtgtattg ggtgcgcgac tcggttagcg gcctgcgcgt gcccgtgcgc 16380 acccgccccc cgcgcaacta gattgcaaga aaaaactact tagactcgta ctgttgtatg 16440 tatccagcgg cggcggcgcg caacgaagct atgtccaagc gcaaaatcaa agaagagatg 16500 ctccaggtca tcgcgccgga gatctatggc cccccgaaga aggaagagca ggattacaag 16560 ccccgaaagc taaagcgggt caaaaagaaa aagaaagatg atgatgatga acttgacgac 16620 gaggtggaac tgctgcacgc taccgcgccc aggcgacggg tacagtggaa aggtcgacgc 16680 gtaaaacgtg ttttgcgacc cggcaccacc gtagtcttta cgcccggtga gcgctccacc 16740 cgcacctaca agcgcgtgta tgatgaggtg tacggcgacg aggacctgct tgagcaggcc 16800 aacgagcgcc tcggggagtt tgcctacgga aagcggcata aggacatgct ggcgttgccg 16860 ctggacgagg gcaacccaac acctagccta aagcccgtaa cactgcagca ggtgctgccc 16920 gcgcttgcac cgtccgaaga aaagcgcggc ctaaagcgcg agtctggtga cttggcaccc 16980 accgtgcagc tgatggtacc caagcgccag cgactggaag atgtcttgga aaaaatgacc 17040 gtggaacctg ggctggagcc cgaggtccgc gtgcggccaa tcaagcaggt ggcgccggga 17100 ctgggcgtgc agaccgtgga cgttcagata cccactacca gtagcaccag tattgccacc 17160 gccacagagg gcatggagac acaaacgtcc ccggttgcct cagcggtggc ggatgccgcg 17220 gtgcaggcgg tcgctgcggc cgcgtccaag acctctacgg aggtgcaaac ggacccgtgg 17280 atgtttcgcg tttcagcccc ccggcgcccg cgccgttcga ggaagtacgg cgccgccagc 17340 gcgctactgc ccgaatatgc cctacatcct tccattgcgc ctacccccgg ctatcgtggc 17400 tacacctacc gccccagaag acgagcaact acccgacgcc gaaccaccac tggaacccgc 17460 cgccgccgtc gccgtcgcca gcccgtgctg gccccgattt ccgtgcgcag ggtggctcgc 17520

gaaggaggca ggaccctggt gctgccaaca gcgcgctacc accccagcat cgtttaaaag 17580 ccggtctttg tggttcttgc agatatggcc ctcacctgcc gcctccgttt cccggtgccg 17640 ggattccgag gaagaatgca ccgtaggagg ggcatggccg gccacggcct gacgggcggc 17700 atgcgtcgtg cgcaccaccg gcggcggcgc gcgtcgcacc gtcgcatgcg cggcggtatc 17760 ctgcccctcc ttattccact gatcgccgcg gcgattggcg ccgtgcccgg aattgcatcc 17820 gtggccttgc aggcgcagag acactgatta aaaacaagtt gcatgtggaa aaatcaaaat 17880 aaaaagtctg gactctcacg ctcgcttggt cctgtaacta ttttgtagaa tggaagacat 17940 caactttgcg tctctggccc cgcgacacgg ctcgcgcccg ttcatgggaa actggcaaga 18000 tatcggcacc agcaatatga gcggtggcgc cttcagctgg ggctcgctgt ggagcggcat 18060 taaaaatttc ggttccaccg ttaagaacta tggcagcaag gcctggaaca gcagcacagg 18120 ccagatgctg agggataagt tgaaagagca aaatttccaa caaaaggtgg tagatggcct 18180 ggcctctggc attagcgggg tggtggacct ggccaaccag gcagtgcaaa ataagattaa 18240 cagtaagctt gatccccgcc ctcccgtaga ggagcctcca ccggccgtgg agacagtgtc 18300 tccagagggg cgtggcgaaa agcgtccgcg ccccgacagg gaagaaactc tggtgacgca 18360 aatagacgag cctccctcgt acgaggaggc actaaagcaa ggcctgccca ccacccgtcc 18420 catcgcgccc atggctaccg gagtgctggg ccagcacaca cccgtaacgc tggacctgcc 18480 tccccccgcc gacacccagc agaaacctgt gctgccaggc ccgaccgccg ttgttgtaac 18540 ccgtcctagc cgcgcgtccc tgcgccgcgc cgccagcggt ccgcgatcgt tgcggcccgt 18600 agccagtggc aactggcaaa gcacactgaa cagcatcgtg ggtctggggg tgcaatccct 18660 gaagcgccga cgatgcttct gatagctaac gtgtcgtatg tgtgtcatgt atgcgtccat 18720 gtcgccgcca gaggagctgc tgagccgccg cgcgcccgct ttccaagatg gctacccctt 18780 cgatgatgcc gcagtggtct tacatgcaca tctcgggcca ggacgcctcg gagtacctga 18840 gccccgggct ggtgcagttt gcccgcgcca ccgagacgta cttcagcctg aataacaagt 18900 ttagaaaccc cacggtggcg cctacgcacg acgtgaccac agaccggtcc cagcgtttga 18960 cgctgcggtt catccctgtg gaccgtgagg atactgcgta ctcgtacaag gcgcggttca 19020 ccctagctgt gggtgataac cgtgtgctgg acatggcttc cacgtacttt gacatccgcg 19080 gcgtgctgga caggggccct acttttaagc cctactctgg cactgcctac aacgccctgg 19140 ctcccaaggg tgccccaaat ccttgcgaat gggatgaagc tgctactgct cttgaaataa 19200 acctagaaga agaggacgat gacaacgaag acgaagtaga cgagcaagct gagcagcaaa 19260 aaactcacgt atttgggcag gcgccttatt ctggtataaa tattacaaag gagggtattc 19320 aaataggtgt cgaaggtcaa acacctaaat atgccgataa aacatttcaa cctgaacctc 19380 aaataggaga atctcagtgg tacgaaacag aaattaatca tgcagctggg agagtcctaa 19440 aaaagactac cccaatgaaa ccatgttacg gttcatatgc aaaacccaca aatgaaaatg 19500 gagggcaagg cattcttgta aagcaacaaa atggaaagct agaaagtcaa gtggaaatgc 19560 aatttttctc aactactgag gcagccgcag gcaatggtga taacttgact cctaaagtgg 19620 tattgtacag tgaagatgta gatatagaaa ccccagacac tcatatttct tacatgccca 19680 ctattaagga aggtaactca cgagaactaa tgggccaaca atctatgccc aacaggccta 19740 attacattgc ttttagggac aattttattg gtctaatgta ttacaacagc acgggtaata 19800 tgggtgttct ggcgggccaa gcatcgcagt tgaatgctgt tgtagatttg caagacagaa 19860 acacagagct ttcataccag cttttgcttg attccattgg tgatagaacc aggtactttt 19920 ctatgtggaa tcaggctgtt gacagctatg atccagatgt tagaattatt gaaaatcatg 19980 gaactgaaga tgaacttcca aattactgct ttccactggg aggtgtgatt aatacagaga 20040 ctcttaccaa ggtaaaacct aaaacaggtc aggaaaatgg atgggaaaaa gatgctacag 20100 aattttcaga taaaaatgaa ataagagttg gaaataattt tgccatggaa atcaatctaa 20160 atgccaacct gtggagaaat ttcctgtact ccaacatagc gctgtatttg cccgacaagc 20220 taaagtacag tccttccaac gtaaaaattt ctgataaccc aaacacctac gactacatga 20280 acaagcgagt ggtggctccc gggctagtgg actgctacat taaccttgga gcacgctggt 20340 cccttgacta tatggacaac gtcaacccat ttaaccacca ccgcaatgct ggcctgcgct 20400 accgctcaat gttgctgggc aatggtcgct atgtgccctt ccacatccag gtgcctcaga 20460 agttctttgc cattaaaaac ctccttctcc tgccgggctc atacacctac gagtggaact 20520 tcaggaagga tgttaacatg gttctgcaga gctccctagg aaatgaccta agggttgacg 20580 gagccagcat taagtttgat agcatttgcc tttacgccac cttcttcccc atggcccaca 20640 acaccgcctc cacgcttgag gccatgctta gaaacgacac caacgaccag tcctttaacg 20700 actatctctc cgccgccaac atgctctacc ctatacccgc caacgctacc aacgtgccca 20760 tatccatccc ctcccgcaac tgggcggctt tccgcggctg ggccttcacg cgccttaaga 20820 ctaaggaaac cccatcactg ggctcgggct acgaccctta ttacacctac tctggctcta 20880 taccctacct agatggaacc ttttacctca accacacctt taagaaggtg gccattacct 20940 ttgactcttc tgtcagctgg cctggcaatg accgcctgct tacccccaac gagtttgaaa 21000 ttaagcgctc agttgacggg gagggttaca acgttgccca gtgtaacatg accaaagact 21060 ggttcctggt acaaatgcta gctaactata acattggcta ccagggcttc tatatcccag 21120 agagctacaa ggaccgcatg tactccttct ttagaaactt ccagcccatg agccgtcagg 21180 tggtggatga tactaaatac aaggactacc aacaggtggg catcctacac caacacaaca 21240 actctggatt tgttggctac cttgccccca ccatgcgcga aggacaggcc taccctgcta 21300 acttccccta tccgcttata ggcaagaccg cagttgacag cattacccag aaaaagtttc 21360 tttgcgatcg caccctttgg cgcatcccat tctccagtaa ctttatgtcc atgggcgcac 21420 tcacagacct gggccaaaac cttctctacg ccaactccgc ccacgcgcta gacatgactt 21480 ttgaggtgga tcccatggac gagcccaccc ttctttatgt tttgtttgaa gtctttgacg 21540 tggtccgtgt gcaccagccg caccgcggcg tcatcgaaac cgtgtacctg cgcacgccct 21600 tctcggccgg caacgccaca acataaagaa gcaagcaaca tcaacaacag ctgccgccat 21660 gggctccagt gagcaggaac tgaaagccat tgtcaaagat cttggttgtg ggccatattt 21720 tttgggcacc tatgacaagc gctttccagg ctttgtttct ccacacaagc tcgcctgcgc 21780 catagtcaat acggccggtc gcgagactgg gggcgtacac tggatggcct ttgcctggaa 21840 cccgcactca aaaacatgct acctctttga gccctttggc ttttctgacc agcgactcaa 21900 gcaggtttac cagtttgagt acgagtcact cctgcgccgt agcgccattg cttcttcccc 21960 cgaccgctgt ataacgctgg aaaagtccac ccaaagcgta caggggccca actcggccgc 22020 ctgtggacta ttctgctgca tgtttctcca cgcctttgcc aactggcccc aaactcccat 22080 ggatcacaac cccaccatga accttattac cggggtaccc aactccatgc tcaacagtcc 22140 ccaggtacag cccaccctgc gtcgcaacca ggaacagctc tacagcttcc tggagcgcca 22200 ctcgccctac ttccgcagcc acagtgcgca gattaggagc gccacttctt tttgtcactt 22260 gaaaaacatg taaaaataat gtactagaga cactttcaat aaaggcaaat gcttttattt 22320 gtacactctc gggtgattat ttacccccac ccttgccgtc tgcgccgttt aaaaatcaaa 22380 ggggttctgc cgcgcatcgc tatgcgccac tggcagggac acgttgcgat actggtgttt 22440 agtgctccac ttaaactcag gcacaaccat ccgcggcagc tcggtgaagt tttcactcca 22500 caggctgcgc accatcacca acgcgtttag caggtcgggc gccgatatct tgaagtcgca 22560 gttggggcct ccgccctgcg cgcgcgagtt gcgatacaca gggttgcagc actggaacac 22620 tatcagcgcc gggtggtgca cgctggccag cacgctcttg tcggagatca gatccgcgtc 22680 caggtcctcc gcgttgctca gggcgaacgg agtcaacttt ggtagctgcc ttcccaaaaa 22740 gggcgcgtgc ccaggctttg agttgcactc gcaccgtagt ggcatcaaaa ggtgaccgtg 22800 cccggtctgg gcgttaggat acagcgcctg cataaaagcc ttgatctgct taaaagccac 22860 ctgagccttt gcgccttcag agaagaacat gccgcaagac ttgccggaaa actgattggc 22920 cggacaggcc gcgtcgtgca cgcagcacct tgcgtcggtg ttggagatct gcaccacatt 22980 tcggccccac cggttcttca cgatcttggc cttgctagac tgctccttca gcgcgcgctg 23040 cccgttttcg ctcgtcacat ccatttcaat cacgtgctcc ttatttatca taatgcttcc 23100 gtgtagacac ttaagctcgc cttcgatctc agcgcagcgg tgcagccaca acgcgcagcc 23160 cgtgggctcg tgatgcttgt aggtcacctc tgcaaacgac tgcaggtacg cctgcaggaa 23220 tcgccccatc atcgtcacaa aggtcttgtt gctggtgaag gtcagctgca acccgcggtg 23280 ctcctcgttc agccaggtct tgcatacggc cgccagagct tccacttggt caggcagtag 23340 tttgaagttc gcctttagat cgttatccac gtggtacttg tccatcagcg cgcgcgcagc 23400 ctccatgccc ttctcccacg cagacacgat cggcacactc agcgggttca tcaccgtaat 23460 ttcactttcc gcttcgctgg gctcttcctc ttcctcttgc gtccgcatac cacgcgccac 23520 tgggtcgtct tcattcagcc gccgcactgt gcgcttacct cctttgccat gcttgattag 23580 caccggtggg ttgctgaaac ccaccatttg tagcgccaca tcttctcttt cttcctcgct 23640 gtccacgatt acctctggtg atggcgggcg ctcgggcttg ggagaagggc gcttcttttt 23700 cttcttgggc gcaatggcca aatccgccgc cgaggtcgat ggccgcgggc tgggtgtgcg 23760 cggcaccagc gcgtcttgtg atgagtcttc ctcgtcctcg gactcgatac gccgcctcat 23820 ccgctttttt gggggcgccc ggggaggcgg cggcgacggg gacggggacg acacgtcctc 23880 catggttggg ggacgtcgcg ccgcaccgcg tccgcgctcg ggggtggttt cgcgctgctc 23940 ctcttcccga ctggccattt ccttctccta taggcagaaa aagatcatgg agtcagtcga 24000 gaagaaggac agcctaaccg ccccctctga gttcgccacc accgcctcca ccgatgccgc 24060 caacgcgcct accaccttcc ccgtcgaggc acccccgctt gaggaggagg aagtgattat 24120 cgagcaggac ccaggttttg taagcgaaga cgacgaggac cgctcagtac caacagagga 24180 taaaaagcaa gaccaggaca acgcagaggc aaacgaggaa caagtcgggc ggggggacga 24240 aaggcatggc gactacctag atgtgggaga cgacgtgctg ttgaagcatc tgcagcgcca 24300 gtgcgccatt atctgcgacg cgttgcaaga gcgcagcgat gtgcccctcg ccatagcgga 24360 tgtcagcctt gcctacgaac gccacctatt ctcaccgcgc gtacccccca aacgccaaga 24420 aaacggcaca tgcgagccca acccgcgcct caacttctac cccgtatttg ccgtgccaga 24480 ggtgcttgcc acctatcaca tctttttcca aaactgcaag atacccctat cctgccgtgc 24540 caaccgcagc cgagcggaca agcagctggc cttgcggcag ggcgctgtca tacctgatat 24600 cgcctcgctc aacgaagtgc caaaaatctt tgagggtctt ggacgcgacg agaagcgcgc 24660 ggcaaacgct ctgcaacagg aaaacagcga aaatgaaagt cactctggag tgttggtgga 24720 actcgagggt gacaacgcgc gcctagccgt actaaaacgc agcatcgagg tcacccactt 24780 tgcctacccg gcacttaacc taccccccaa ggtcatgagc acagtcatga gtgagctgat 24840 cgtgcgccgt gcgcagcccc tggagaggga tgcaaatttg caagaacaaa cagaggaggg 24900 cctacccgca gttggcgacg agcagctagc gcgctggctt caaacgcgcg agcctgccga 24960 cttggaggag cgacgcaaac taatgatggc cgcagtgctc gttaccgtgg agcttgagtg 25020

catgcagcgg ttctttgctg acccggagat gcagcgcaag ctagaggaaa cattgcacta 25080 cacctttcga cagggctacg tacgccaggc ctgcaagatc tccaacgtgg agctctgcaa 25140 cctggtctcc taccttggaa ttttgcacga aaaccgcctt gggcaaaacg tgcttcattc 25200 cacgctcaag ggcgaggcgc gccgcgacta cgtccgcgac tgcgtttact tatttctatg 25260 ctacacctgg cagacggcca tgggcgtttg gcagcagtgc ttggaggagt gcaacctcaa 25320 ggagctgcag aaactgctaa agcaaaactt gaaggaccta tggacggcct tcaacgagcg 25380 ctccgtggcc gcgcacctgg cggacatcat tttccccgaa cgcctgctta aaaccctgca 25440 acagggtctg ccagacttca ccagtcaaag catgttgcag aactttagga actttatcct 25500 agagcgctca ggaatcttgc ccgccacctg ctgtgcactt cctagcgact ttgtgcccat 25560 taagtaccgc gaatgccctc cgccgctttg gggccactgc taccttctgc agctagccaa 25620 ctaccttgcc taccactctg acataatgga agacgtgagc ggtgacggtc tactggagtg 25680 tcactgtcgc tgcaacctat gcaccccgca ccgctccctg gtttgcaatt cgcagctgct 25740 taacgaaagt caaattatcg gtacctttga gctgcagggt ccctcgcctg acgaaaagtc 25800 cgcggctccg gggttgaaac tcactccggg gctgtggacg tcggcttacc ttcgcaaatt 25860 tgtacctgag gactaccacg cccacgagat taggttctac gaagaccaat cccgcccgcc 25920 taatgcggag cttaccgcct gcgtcattac ccagggccac attcttggcc aattgcaagc 25980 catcaacaaa gcccgccaag agtttctgct acgaaaggga cggggggttt acttggaccc 26040 ccagtccggc gaggagctca acccaatccc cccgccgccg cagccctatc agcagcagcc 26100 gcgggccctt gcttcccagg atggcaccca aaaagaagct gcagctgccg ccgccaccca 26160 cggacgagga ggaatactgg gacagtcagg cagaggaggt tttggacgag gaggaggagg 26220 acatgatgga agactgggag agcctagacg aggaagcttc cgaggtcgaa gaggtgtcag 26280 acgaaacacc gtcaccctcg gtcgcattcc cctcgccggc gccccagaaa tcggcaaccg 26340 gttccagcat ggctacaacc tccgctcctc aggcgccgcc ggcactgccc gttcgccgac 26400 ccaaccgtag atgggacacc actggaacca gggccggtaa gtccaagcag ccgccgccgt 26460 tagcccaaga gcaacaacag cgccaaggct accgctcatg gcgcgggcac aagaacgcca 26520 tagttgcttg cttgcaagac tgtgggggca acatctcctt cgcccgccgc tttcttctct 26580 accatcacgg cgtggccttc ccccgtaaca tcctgcatta ctaccgtcat ctctacagcc 26640 catactgcac cggcggcagc ggcagcaaca gcagcggcca cacagaagca aaggcgaccg 26700 gatagcaaga ctctgacaaa gcccaagaaa tccacagcgg cggcagcagc aggaggagga 26760 gcgctgcgtc tggcgcccaa cgaacccgta tcgacccgcg agcttagaaa caggattttt 26820 cccactctgt atgctatatt tcaacagagc aggggccaag aacaagagct gaaaataaaa 26880 aacaggtctc tgcgatccct cacccgcagc tgcctgtatc acaaaagcga agatcagctt 26940 cggcgcacgc tggaagacgc ggaggctctc ttcagtaaat actgcgcgct gactcttaag 27000 gactagtttc gcgccctttc tcaaatttaa gcgcgaaaac tacgtcatct ccagcggcca 27060 cacccggcgc cagcacctgt tgtcagcgcc attatgagca aggaaattcc cacgccctac 27120 atgtggagtt accagccaca aatgggactt gcggctggag ctgcccaaga ctactcaacc 27180 cgaataaact acatgagcgc gggaccccac atgatatccc gggtcaacgg aatacgcgcc 27240 caccgaaacc gaattctcct ggaacaggcg gctattacca ccacacctcg taataacctt 27300 aatccccgta gttggcccgc tgccctggtg taccaggaaa gtcccgctcc caccactgtg 27360 gtacttccca gagacgccca ggccgaagtt cagatgacta actcaggggc gcagcttgcg 27420 ggcggctttc gtcacagggt gcggtcgccc gggcagggta taactcacct gacaatcaga 27480 gggcgaggta ttcagctcaa cgacgagtcg gtgagctcct cgcttggtct ccgtccggac 27540 gggacatttc agatcggcgg cgccggccgc tcttcattca cgcctcgtca ggcaatccta 27600 actctgcaga cctcgtcctc tgagccgcgc tctggaggca ttggaactct gcaatttatt 27660 gaggagtttg tgccatcggt ctactttaac cccttctcgg gacctcccgg ccactatccg 27720 gatcaattta ttcctaactt tgacgcggta aaggactcgg cggacggcta cgactgaatg 27780 ttaagtggag aggcagagca actgcgcctg aaacacctgg tccactgtcg ccgccacaag 27840 tgctttgccc gcgactccgg tgagttttgc tactttgaat tgcccgagga tcatatcgag 27900 ggcccggcgc acggcgtccg gcttaccgcc cagggagagc ttgcccgtag cctgattcgg 27960 gagtttaccc agcgccccct gctagttgag cgggacaggg gaccctgtgt tctcactgtg 28020 atttgcaact gtcctaaccc tggattacat caagatcctc tagttaatgt caggtcgcct 28080 aagtcgatta actagagtac ccggggatct tattcccttt aactaataaa aaaaaataat 28140 aaagcatcac ttacttaaaa tcagttagca aatttctgtc cagtttattc agcagcacct 28200 ccttgccctc ctcccagctc tggtattgca gcttcctcct ggctgcaaac tttctccaca 28260 atctaaatgg aatgtcagtt tcctcctgtt cctgtccatc cgcacccact atcttcatgt 28320 tgttgcagat gaagcgcgca agaccgtctg aagatacctt caaccccgtg tatccatatg 28380 acacggaaac cggtcctcca actgtgcctt ttcttactcc tccctttgta tcccccaatg 28440 ggtttcaaga gagtccccct ggggtactct ctttgcgcct atccgaacct ctagttacct 28500 ccaatggcat gcttgcgctc aaaatgggca acggcctctc tctggacgag gccggcaacc 28560 ttacctccca aaatgtaacc actgtgagcc cacctctcaa aaaaaccaag tcaaacataa 28620 acctggaaat atctgcaccc ctcacagtta cctcagaagc cctaactgtg gctgccgccg 28680 cacctctaat ggtcgcgggc aacacactca ccatgcaatc acaggccccg ctaaccgtgc 28740 acgactccaa acttagcatt gccacccaag gacccctcac agtgtcagaa ggaaagctag 28800 ccctgcaaac atcaggcccc ctcaccacca ccgatagcag tacccttact atcactgcct 28860 caccccctct aactactgcc actggtagct tgggcattga cttgaaagag cccatttata 28920 cacaaaatgg aaaactagga ctaaagtacg gggctccttt gcatgtaaca gacgacctaa 28980 acactttgac cgtagcaact ggtccaggtg tgactattaa taatacttcc ttgcaaacta 29040 aagttactgg agccttgggt tttgattcac aaggcaatat gcaacttaat gtagcaggag 29100 gactaaggat tgattctcaa aacagacgcc ttatacttga tgttagttat ccgtttgatg 29160 ctcaaaacca actaaatcta agactaggac agggccctct ttttataaac tcagcccaca 29220 acttggatat taactacaac aaaggccttt acttgtttac agcttcaaac aattccaaaa 29280 agcttgaggt taacctaagc actgccaagg ggttgatgtt tgacgctaca gccatagcca 29340 ttaatgcagg agatgggctt gaatttggtt cacctaatgc accaaacaca aatcccctca 29400 aaacaaaaat tggccatggc ctagaatttg attcaaacaa ggctatggtt cctaaactag 29460 gaactggcct tagttttgac agcacaggtg ccattacagt aggaaacaaa aataatgata 29520 agctaacttt gtggaccaca ccagctccat ctcctaactg tagactaaat gcagagaaag 29580 atgctaaact cactttggtc ttaacaaaat gtggcagtca aatacttgct acagtttcag 29640 ttttggctgt taaaggcagt ttggctccaa tatctggaac agttcaaagt gctcatctta 29700 ttataagatt tgacgaaaat ggagtgctac taaacaattc cttcctggac ccagaatatt 29760 ggaactttag aaatggagat cttactgaag gcacagccta tacaaacgct gttggattta 29820 tgcctaacct atcagcttat ccaaaatctc acggtaaaac tgccaaaagt aacattgtca 29880 gtcaagttta cttaaacgga gacaaaacta aacctgtaac actaaccatt acactaaacg 29940 gtacacagga aacaggagac acaactccaa gtgcatactc tatgtcattt tcatgggact 30000 ggtctggcca caactacatt aatgaaatat ttgccacatc ctcttacact ttttcataca 30060 ttgcccaaga ataaagaatc gtttgtgtta tgtttcaacg tgtttatttt tcaattgcag 30120 aaaatttcaa gtcatttttc attcagtagt atagccccac caccacatag cttatacaga 30180 tcaccgtacc ttaatcaaac tcacagaacc ctagtattca acctgccacc tccctcccaa 30240 cacacagagt acacagtcct ttctccccgg ctggccttaa aaagcatcat atcatgggta 30300 acagacatat tcttaggtgt tatattccac acggtttcct gtcgagccaa acgctcatca 30360 gtgatattaa taaactcccc gggcagctca cttaagttca tgtcgctgtc cagctgctga 30420 gccacaggct gctgtccaac ttgcggttgc ttaacgggcg gcgaaggaga agtccacgcc 30480 tacatggggg tagagtcata atcgtgcatc aggatagggc ggtggtgctg cagcagcgcg 30540 cgaataaact gctgccgccg ccgctccgtc ctgcaggaat acaacatggc agtggtctcc 30600 tcagcgatga ttcgcaccgc ccgcagcata aggcgccttg tcctccgggc acagcagcgc 30660 accctgatct cacttaaatc agcacagtaa ctgcagcaca gcaccacaat attgttcaaa 30720 atcccacagt gcaaggcgct gtatccaaag ctcatggcgg ggaccacaga acccacgtgg 30780 ccatcatacc acaagcgcag gtagattaag tggcgacccc tcataaacac gctggacata 30840 aacattacct cttttggcat gttgtaattc accacctccc ggtaccatat aaacctctga 30900 ttaaacatgg cgccatccac caccatccta aaccagctgg ccaaaacctg cccgccggct 30960 atacactgca gggaaccggg actggaacaa tgacagtgga gagcccagga ctcgtaacca 31020 tggatcatca tgctcgtcat gatatcaatg ttggcacaac acaggcacac gtgcatacac 31080 ttcctcagga ttacaagctc ctcccgcgtt agaaccatat cccagggaac aacccattcc 31140 tgaatcagcg taaatcccac actgcaggga agacctcgca cgtaactcac gttgtgcatt 31200 gtcaaagtgt tacattcggg cagcagcgga tgatcctcca gtatggtagc gcgggtttct 31260 gtctcaaaag gaggtagacg atccctactg tacggagtgc gccgagacaa ccgagatcgt 31320 gttggtcgta gtgtcatgcc aaatggaacg ccggacgtag tcatatttcc tgaagcaaaa 31380 ccaggtgcgg gcgtgacaaa cagatctgcg tctccggtct cgccgcttag atcgctctgt 31440 gtagtagttg tagtatatcc actctctcaa agcatccagg cgccccctgg cttcgggttc 31500 tatgtaaact ccttcatgcg ccgctgccct gataacatcc accaccgcag aataagccac 31560 acccagccaa cctacacatt cgttctgcga gtcacacacg ggaggagcgg gaagagctgg 31620 aagaaccatg tttttttttt tattccaaaa gattatccaa aacctcaaaa tgaagatcta 31680 ttaagtgaac gcgctcccct ccggtggcgt ggtcaaactc tacagccaaa gaacagataa 31740 tggcatttgt aagatgttgc acaatggctt ccaaaaggca aacggccctc acgtccaagt 31800 ggacgtaaag gctaaaccct tcagggtgaa tctcctctat aaacattcca gcaccttcaa 31860 ccatgcccaa ataattctca tctcgccacc ttctcaatat atctctaagc aaatcccgaa 31920 tattaagtcc ggccattgta aaaatctgct ccagagcgcc ctccaccttc agcctcaagc 31980 agcgaatcat gattgcaaaa attcaggttc ctcacagacc tgtataagat tcaaaagcgg 32040 aacattaaca aaaataccgc gatcccgtag gtcccttcgc agggccagct gaacataatc 32100 gtgcaggtct gcacggacca gcgcggccac ttccccgcca ggaaccatga caaaagaacc 32160 cacactgatt atgacacgca tactcggagc tatgctaacc agcgtagccc cgatgtaagc 32220 ttgttgcatg ggcggcgata taaaatgcaa ggtgctgctc aaaaaatcag gcaaagcctc 32280 gcgcaaaaaa gaaagcacat cgtagtcatg ctcatgcaga taaaggcagg taagctccgg 32340 aaccaccaca gaaaaagaca ccatttttct ctcaaacatg tctgcgggtt tctgcataaa 32400 cacaaaataa aataacaaaa aaacatttaa acattagaag cctgtcttac aacaggaaaa 32460 acaaccctta taagcataag acggactacg gccatgccgg cgtgaccgta aaaaaactgg 32520 tcaccgtgat taaaaagcac caccgacagc tcctcggtca tgtccggagt cataatgtaa 32580

gactcggtaa acacatcagg ttgattcaca tcggtcagtg ctaaaaagcg accgaaatag 32640 cccgggggaa tacatacccg caggcgtaga gacaacatta cagcccccat aggaggtata 32700 acaaaattaa taggagagaa aaacacataa acacctgaaa aaccctcctg cctaggcaaa 32760 atagcaccct cccgctccag aacaacatac agcgcttcca cagcggcagc cataacagtc 32820 agccttacca gtaaaaaaga aaacctatta aaaaaacacc actcgacacg gcaccagctc 32880 aatcagtcac agtgtaaaaa agggccaagt gcagagcgag tatatatagg actaaaaaat 32940 gacgtaacgg ttaaagtcca caaaaaacac ccagaaaacc gcacgcgaac ctacgcccag 33000 aaacgaaagc caaaaaaccc acaacttcct caaatcgtca cttccgtttt cccacgttac 33060 gtcacttccc attttaagaa aactacaatt cccaacacat acaagttact ccgccctaaa 33120 acctacgtca cccgccccgt tcccacgccc cgcgccacgt cacaaactcc accccctcat 33180 tatcatattg gcttcaatcc aaaataaggt atattattga tgatg 33225 <210> SEQ ID NO 95 <211> LENGTH: 34665 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 95 ttttggattg aagccaatat gataatgagg gggtggagtt tgtgacgtgg cgcggggcgt 60 gggaacgggg cgggtgacgt agtagtgtgg cggaagtgtg atgttgcaag tgtggcggaa 120 cacatgtaag cgacggatgt ggcaaaagtg acgtttttgg tgtgcgccgg tgttttgggc 180 gtaaccgagt aagatttggc cattttcgcg ggaaaactga ataagaggaa gtgaaatctg 240 aataattttg tgttactcat agcgcgtaat atttgtctag ggccgcgggg actttgaccg 300 tttacgtgga gactcgccca ggtgtttttc tcaggtgttt tccgcgttcc gggtcaaagt 360 tggcgtttta ttattatagt cagctgacgt gtagtgtatt tatacccggt gagttcctca 420 agaggccact cttgagtgcc agcgagtaga gttttctcct ccgagccgct ccgacaccgg 480 gactgaaaat gagacatatt atctgccacg gaggtgttat taccgaagaa atggccgcca 540 gtcttttgga ccagctgatc gaagaggtac tggctgataa tcttccacct cctagccatt 600 ttgaaccacc tacccttcac gaactgtatg atttagacgt gacggccccc gaagatccca 660 acgaggaggc ggtttcgcag atttttcccg actctgtaat gttggcggtg caggaaggga 720 ttgacttact cacttttccg ccggcgcccg gttctccgga gccgcctcac ctttcccggc 780 agcccgagca gccggagcag agagccttgg gtccggtttc tatgccaaac cttgtaccgg 840 aggtgatcga tcttacctgc cacgaggctg gctttccacc cagtgacgac gaggatgaag 900 agggtgagga gtttgtgtta gattatgtgg agcaccccgg gcacggttgc aggtcttgtc 960 attatcaccg gaggaatacg ggggacccag atattatgtg ttcgctttgc tatatgagga 1020 cctgtggcat gtttgtctac agtaagtgaa aattatgggc agtgggtgat agagtggtgg 1080 gtttggtgtg gtaatttttt ttttaatttt tacagttttg tggtttaaag aattttgtat 1140 tgtgattttt ttaaaaggtc ctgtgtctga acctgagcct gagcccgagc cagaaccgga 1200 gcctgcaaga cctacccgcc gtcctaaaat ggcgcctgct atcctgagac gcccgacatc 1260 acctgtgtct agagaatgca atagtagtac ggatagctgt gactccggtc cttctaacac 1320 acctcctgag atacacccgg tggtcccgct gtgccccatt aaaccagttg ccgtgagagt 1380 tggtgggcgt cgccaggctg tggaatgtat cgaggacttg cttaacgagc ctgggcaacc 1440 tttggacttg agctgtaaac gccccaggcc ataaggtgta aacctgtgat tgcgtgtgtg 1500 gttaacgcct ttgtttgctg aatgagttga tgtaagttta ataaagggtg agataatgtt 1560 taacttgcat ggcgtgttaa atggggcggg gcttaaaggg tatataatgc gccgtgggct 1620 aatcttggtt acatctgacc tcgtcgacgc caccatgtgt caccagcagc tcgtgattag 1680 ctggttcagc ctggtgtttc tggctagccc tctggtggcc atctgggagc tgaagaagga 1740 cgtgtacgtg gtggagctcg actggtaccc tgacgctccc ggcgagatgg tcgtgctgac 1800 ctgcgacacc cctgaggaag atggcatcac ctggaccctg gatcaaagct ccgaagtgct 1860 cggcagcggc aagacactca ccatccaggt gaaagagttc ggagacgccg gccagtacac 1920 ctgccacaaa ggcggcgagg tgctgtccca ttccctgctg ctgctgcaca agaaagagga 1980 tggcatctgg tccaccgaca tcctgaagga ccagaaggaa cccaagaaca agacctttct 2040 gagatgtgag gccaagaact acagcggcag gttcacctgc tggtggctga caacaatctc 2100 caccgacctg accttcagcg tcaagagcag caggggcagc agcgaccctc aaggcgtgac 2160 atgtggagcc gctaccctga gcgctgagag agtcaggggc gacaataagg agtacgagta 2220 ctccgtggaa tgccaggagg actccgcctg ccctgccgcc gaagagtccc tccctatcga 2280 agtgatggtt gatgccgtgc acaagctcaa gtatgagaat tacaccagca gctttttcat 2340 cagggacatc atcaagcccg acccccccaa aaacctccag ctgaaacccc tcaagaatag 2400 caggcaggtg gaggtctcct gggagtatcc tgacacctgg agcacccccc acagctactt 2460 ctccctgacc ttctgtgtgc aggtgcaggg caagagcaaa agggagaaga aggatagggt 2520 ctttaccgac aagaccagcg ccacagtgat ctgcaggaag aacgccagca tttccgtcag 2580 ggcccaggac aggtactaca gcagcagctg gtccgagtgg gctagcgtgc cttgttccgg 2640 cggcggagga tctggcggag gcggaagtgg cggagggggc tctagaaacc tccccgtggc 2700 cacacccgac cctggcatgt tcccctgcct ccaccacagc cagaacctgc tgagagccgt 2760 gagcaatatg ctgcagaagg ccaggcaaac cctggagttc tacccctgta cctccgagga 2820 gattgaccat gaggacatca caaaggacaa aaccagcacc gtggaggcct gtctccccct 2880 cgaactgacc aagaacgagt cctgcctgaa ctccagggag acatccttca tcaccaacgg 2940 ctcctgcctg gcctccagaa agaccagctt catgatggcc ctctgcctga gcagcatcta 3000 cgaggacctc aagatgtacc aggtggagtt taaaacaatg aacgccaagc tcctcatgga 3060 ccctaagagg cagattttcc tcgaccagaa tatgctggct gtcattgacg agctgatgca 3120 ggccctcaat ttcaactccg agaccgtccc ccagaagtcc tccctggaag agcccgactt 3180 ttacaagacc aagatcaagc tctgcatcct gctgcacgcc ttcagaatta gagccgtgac 3240 cattgacagg gtgatgagct acctcaacgc ctcctgatga ctcgagtcac caggcgcttt 3300 tccaagagaa ggtcatcaag actttggatt tttccacacc ggggcgcgct gcggctgctg 3360 ttgctttttt gagttttata aaggataaat ggagcgaaga aacccatctg agcggggggt 3420 acctgctgga ttttctggcc atgcatctgt ggagagcggt tgtgagacac aagaatcgcc 3480 tgctactgtt gtcttccgtc cgcccggcga taataccgac ggaggagcag cagcagcagc 3540 aggaggaagc caggcggcgg cggcaggagc agagcccatg gaacccgaga gccggcctgg 3600 accctcggga atgaatgttg tacaggtggc tgaactgtat ccagaactga gacgcatttt 3660 gacaattaca gaggatgggc aggggctaaa gggggtaaag agggagcggg gggcttgtga 3720 ggctacagag gaggctagga atctagcttt tagcttaatg accagacacc gtcctgagtg 3780 tattactttt caacagatca aggataattg cgctaatgag cttgatctgc tggcgcagaa 3840 gtattccata gagcagctga ccacttactg gctgcagcca ggggatgatt ttgaggaggc 3900 tattagggta tatgcaaagg tggcacttag gccagattgc aagtacaaga tcagcaaact 3960 tgtaaatatc aggaattgtt gctacatttc tgggaacggg gccgaggtgg agatagatac 4020 ggaggatagg gtggccttta gatgtagcat gataaatatg tggccggggg tgcttggcat 4080 ggacggggtg gttattatga atgtaaggtt tactggcccc aattttagcg gtacggtttt 4140 cctggccaat accaacctta tcctacacgg tgtaagcttc tatgggttta acaatacctg 4200 tgtggaagcc tggaccgatg taagggttcg gggctgtgcc ttttactgct gctggaaggg 4260 ggtggtgtgt cgccccaaaa gcagggcttc aattaagaaa tgcctctttg aaaggtgtac 4320 cttgggtatc ctgtctgagg gtaactccag ggtgcgccac aatgtggcct ccgactgtgg 4380 ttgcttcatg ctagtgaaaa gcgtggctgt gattaagcat aacatggtat gtggcaactg 4440 cgaggacagg gcctctcaga tgctgacctg ctcggacggc aactgtcacc tgctgaagac 4500 cattcacgta gccagccact ctcgcaaggc ctggccagtg tttgagcata acatactgac 4560 ccgctgttcc ttgcatttgg gtaacaggag gggggtgttc ctaccttacc aatgcaattt 4620 gagtcacact aagatattgc ttgagcccga gagcatgtcc aaggtgaacc tgaacggggt 4680 gtttgacatg accatgaaga tctggaaggt gctgaggtac gatgagaccc gcaccaggtg 4740 cagaccctgc gagtgtggcg gtaaacatat taggaaccag cctgtgatgc tggatgtgac 4800 cgaggagctg aggcccgatc acttggtgct ggcctgcacc cgcgctgagt ttggctctag 4860 cgatgaagat acagattgag gtactgaaat gtgtgggcgt ggcttaaggg tgggaaagaa 4920 tatataaggt gggggtctta tgtagttttg tatctgtttt gcagcagccg ccgccgccat 4980 gagcaccaac tcgtttgatg gaagcattgt gagctcatat ttgacaacgc gcatgccccc 5040 atgggccggg gtgcgtcaga atgtgatggg ctccagcatt gatggtcgcc ccgtcctgcc 5100 cgcaaactct actaccttga cctacgagac cgtgtctgga acgccgttgg agactgcagc 5160 ctccgccgcc gcttcagccg ctgcagccac cgcccgcggg attgtgactg actttgcttt 5220 cctgagcccg cttgcaagca gtgcagcttc ccgttcatcc gcccgcgatg acaagttgac 5280 ggctcttttg gcacaattgg attctttgac ccgggaactt aatgtcgttt ctcagcagct 5340 gttggatctg cgccagcagg tttctgccct gaaggcttcc tcccctccca atgcggttta 5400 aaacataaat aaaaaaccag actctgtttg gatttggatc aagcaagtgt cttgctgtct 5460 ttatttaggg gttttgcgcg cgcggtaggc ccgggaccag cggtctcggt cgttgagggt 5520 cctgtgtatt ttttccagga cgtggtaaag gtgactctgg atgttcagat acatgggcat 5580 aagcccgtct ctggggtgga ggtagcacca ctgcagagct tcatgctgcg gggtggtgtt 5640 gtagatgatc cagtcgtagc aggagcgctg ggcgtggtgc ctaaaaatgt ctttcagtag 5700 caagctgatt gccaggggca ggcccttggt gtaagtgttt acaaagcggt taagctggga 5760 tgggtgcata cgtggggata tgagatgcat cttggactgt atttttaggt tggctatgtt 5820 cccagccata tccctccggg gattcatgtt gtgcagaacc accagcacag tgtatccggt 5880 gcacttggga aatttgtcat gtagcttaga aggaaatgcg tggaagaact tggagacgcc 5940 cttgtgacct ccaagatttt ccatgcattc gtccataatg atggcaatgg gcccacgggc 6000 ggcggcctgg gcgaagatat ttctgggatc actaacgtca tagttgtgtt ccaggatgag 6060 atcgtcatag gccattttta caaagcgcgg gcggagggtg ccagactgcg gtataatggt 6120 tccatccggc ccaggggcgt agttaccctc acagatttgc atttcccacg ctttgagttc 6180 agatgggggg atcatgtcta cctgcggggc gatgaagaaa acggtttccg gggtagggga 6240 gatcagctgg gaagaaagca ggttcctgag cagctgcgac ttaccgcagc cggtgggccc 6300 gtaaatcaca cctattaccg gctgcaactg gtagttaaga gagctgcagc tgccgtcatc 6360 cctgagcagg ggggccactt cgttaagcat gtccctgact cgcatgtttt ccctgaccaa 6420 atccgccaga aggcgctcgc cgcccagcga tagcagttct tgcaaggaag caaagttttt 6480

caacggtttg agaccgtccg ccgtaggcat gcttttgagc gtttgaccaa gcagttccag 6540 gcggtcccac agctcggtca cctgctctac ggcatctcga tccagcatat ctcctcgttt 6600 cgcgggttgg ggcggctttc gctgtacggc agtagtcggt gctcgtccag acgggccagg 6660 gtcatgtctt tccacgggcg cagggtcctc gtcagcgtag tctgggtcac ggtgaagggg 6720 tgcgctccgg gctgcgcgct ggccagggtg cgcttgaggc tggtcctgct ggtgctgaag 6780 cgctgccggt cttcgccctg cgcgtcggcc aggtagcatt tgaccatggt gtcatagtcc 6840 agcccctccg cggcgtggcc cttggcgcgc agcttgccct tggaggaggc gccgcacgag 6900 gggcagtgca gacttttgag ggcgtagagc ttgggcgcga gaaataccga ttccggggag 6960 taggcatccg cgccgcaggc cccgcagacg gtctcgcatt ccacgagcca ggtgagctct 7020 ggccgttcgg ggtcaaaaac caggtttccc ccatgctttt tgatgcgttt cttacctctg 7080 gtttccatga gccggtgtcc acgctcggtg acgaaaaggc tgtccgtgtc cccgtataca 7140 gacttgagag gcctgtcctc gagcggtgtt ccgcggtcct cctcgtatag aaactcggac 7200 cactctgaga caaaggctcg cgtccaggcc agcacgaagg aggctaagtg ggaggggtag 7260 cggtcgttgt ccactagggg gtccactcgc tccagggtgt gaagacacat gtcgccctct 7320 tcggcatcaa ggaaggtgat tggtttgtag gtgtaggcca cgtgaccggg tgttcctgaa 7380 ggggggctat aaaagggggt gggggcgcgt tcgtcctcac tctcttccgc atcgctgtct 7440 gcgagggcca gctgttgggg tgagtactcc ctctgaaaag cgggcatgac ttctgcgcta 7500 agattgtcag tttccaaaaa cgaggaggat ttgatattca cctggcccgc ggtgatgcct 7560 ttgagggtgg ccgcatccat ctggtcagaa aagacaatct ttttgttgtc aagcttggtg 7620 gcaaacgacc cgtagagggc gttggacagc aacttggcga tggagcgcag ggtttggttt 7680 ttgtcgcgat cggcgcgctc cttggccgcg atgtttagct gcacgtattc gcgcgcaacg 7740 caccgccatt cgggaaagac ggtggtgcgc tcgtcgggca ccaggtgcac gcgccaaccg 7800 cggttgtgca gggtgacaag gtcaacgctg gtggctacct ctccgcgtag gcgctcgttg 7860 gtccagcaga ggcggccgcc cttgcgcgag cagaatggcg gtagggggtc tagctgcgtc 7920 tcgtccgggg ggtctgcgtc cacggtaaag accccgggca gcaggcgcgc gtcgaagtag 7980 tctatcttgc atccttgcaa gtctagcgcc tgctgccatg cgcgggcggc aagcgcgcgc 8040 tcgtatgggt tgagtggggg accccatggc atggggtggg tgagcgcgga ggcgtacatg 8100 ccgcaaatgt cgtaaacgta gaggggctct ctgagtattc caagatatgt agggtagcat 8160 cttccaccgc ggatgctggc gcgcacgtaa tcgtatagtt cgtgcgaggg agcgaggagg 8220 tcgggaccga ggttgctacg ggcgggctgc tctgctcgga agactatctg cctgaagatg 8280 gcatgtgagt tggatgatat ggttggacgc tggaagacgt tgaagctggc gtctgtgaga 8340 cctaccgcgt cacgcacgaa ggaggcgtag gagtcgcgca gcttgttgac cagctcggcg 8400 gtgacctgca cgtctagggc gcagtagtcc agggtttcct tgatgatgtc atacttatcc 8460 tgtccctttt ttttccacag ctcgcggttg aggacaaact cttcgcggtc tttccagtac 8520 tcttggatcg gaaacccgtc ggcctccgaa cggtaagagc ctagcatgta gaactggttg 8580 acggcctggt aggcgcagca tcccttttct acgggtagcg cgtatgcctg cgcggccttc 8640 cggagcgagg tgtgggtgag cgcaaaggtg tccctgacca tgactttgag gtactggtat 8700 ttgaagtcag tgtcgtcgca tccgccctgc tcccagagca aaaagtccgt gcgctttttg 8760 gaacgcggat ttggcagggc gaaggtgaca tcgttgaaga gtatctttcc cgcgcgaggc 8820 ataaagttgc gtgtgatgcg gaagggtccc ggcacctcgg aacggttgtt aattacctgg 8880 gcggcgagca cgatctcgtc aaagccgttg atgttgtggc ccacaatgta aagttccaag 8940 aagcgcggga tgcccttgat ggaaggcaat tttttaagtt cctcgtaggt gagctcttca 9000 ggggagctga gcccgtgctc tgaaagggcc cagtctgcaa gatgagggtt ggaagcgacg 9060 aatgagctcc acaggtcacg ggccattagc atttgcaggt ggtcgcgaaa ggtcctaaac 9120 tggcgaccta tggccatttt ttctggggtg atgcagtaga aggtaagcgg gtcttgttcc 9180 cagcggtccc atccaaggtt cgcggctagg tctcgcgcgg cagtcactag aggctcatct 9240 ccgccgaact tcatgaccag catgaagggc acgagctgct tcccaaaggc ccccatccaa 9300 gtataggtct ctacatcgta ggtgacaaag agacgctcgg tgcgaggatg cgagccgatc 9360 gggaagaact ggatctcccg ccaccaattg gaggagtggc tattgatgtg gtgaaagtag 9420 aagtccctgc gacgggccga acactcgtgc tggcttttgt aaaaacgtgc gcagtactgg 9480 cagcggtgca cgggctgtac atcctgcacg aggttgacct gacgaccgcg cacaaggaag 9540 cagagtggga atttgagccc ctcgcctggc gggtttggct ggtggtcttc tacttcggct 9600 gcttgtcctt gaccgtctgg ctgctcgagg ggagttacgg tggatcggac caccacgccg 9660 cgcgagccca aagtccagat gtccgcgcgc ggcggtcgga gcttgatgac aacatcgcgc 9720 agatgggagc tgtccatggt ctggagctcc cgcggcgtca ggtcaggcgg gagctcctgc 9780 aggtttacct cgcatagacg ggtcagggcg cgggctagat ccaggtgata cctaatttcc 9840 aggggctggt tggtggcggc gtcgatggct tgcaagaggc cgcatccccg cggcgcgact 9900 acggtaccgc gcggcgggcg gtgggccgcg ggggtgtcct tggatgatgc atctaaaagc 9960 ggtgacgcgg gcgagccccc ggaggtaggg ggggctccgg acccgccggg agagggggca 10020 ggggcacgtc ggcgccgcgc gcgggcagga gctggtgctg cgcgcgtagg ttgctggcga 10080 acgcgacgac gcggcggttg atctcctgaa tctggcgcct ctgcgtgaag acgacgggcc 10140 cggtgagctt gaacctgaaa gagagttcga cagaatcaat ttcggtgtcg ttgacggcgg 10200 cctggcgcaa aatctcctgc acgtctcctg agttgtcttg ataggcgatc tcggccatga 10260 actgctcgat ctcttcctcc tggagatctc cgcgtccggc tcgctccacg gtggcggcga 10320 ggtcgttgga aatgcgggcc atgagctgcg agaaggcgtt gaggcctccc tcgttccaga 10380 cgcggctgta gaccacgccc ccttcggcat cgcgggcgcg catgaccacc tgcgcgagat 10440 tgagctccac gtgccgggcg aagacggcgt agtttcgcag gcgctgaaag aggtagttga 10500 gggtggtggc ggtgtgttct gccacgaaga agtacataac ccagcgtcgc aacgtggatt 10560 cgttgatatc ccccaaggcc tcaaggcgct ccatggcctc gtagaagtcc acggcgaagt 10620 tgaaaaactg ggagttgcgc gccgacacgg ttaactcctc ctccagaaga cggatgagct 10680 cggcgacagt gtcgcgcacc tcgcgctcaa aggctacagg ggcctcttct tcttcttcaa 10740 tctcctcttc cataagggcc tccccttctt cttcttctgg cggcggtggg ggagggggga 10800 cacggcggcg acgacggcgc accgggaggc ggtcgacaaa gcgctcgatc atctccccgc 10860 ggcgacggcg catggtctcg gtgacggcgc ggccgttctc gcgggggcgc agttggaaga 10920 cgccgcccgt catgtcccgg ttatgggttg gcggggggct gccatgcggc agggatacgg 10980 cgctaacgat gcatctcaac aattgttgtg taggtactcc gccgccgagg gacctgagcg 11040 agtccgcatc gaccggatcg gaaaacctct cgagaaaggc gtctaaccag tcacagtcgc 11100 aaggtaggct gagcaccgtg gcgggcggca gcgggcggcg gtcggggttg tttctggcgg 11160 aggtgctgct gatgatgtaa ttaaagtagg cggtcttgag acggcggatg gtcgacagaa 11220 gcaccatgtc cttgggtccg gcctgctgaa tgcgcaggcg gtcggccatg ccccaggctt 11280 cgttttgaca tcggcgcagg tctttgtagt agtcttgcat gagcctttct accggcactt 11340 cttcttctcc ttcctcttgt cctgcatctc ttgcatctat cgctgcggcg gcggcggagt 11400 ttggccgtag gtggcgccct cttcctccca tgcgtgtgac cccgaagccc ctcatcggct 11460 gaagcagggc taggtcggcg acaacgcgct cggctaatat ggcctgctgc acctgcgtga 11520 gggtagactg gaagtcatcc atgtccacaa agcggtggta tgcgcccgtg ttgatggtgt 11580 aagtgcagtt ggccataacg gaccagttaa cggtctggtg acccggctgc gagagctcgg 11640 tgtacctgag acgcgagtaa gccctcgagt caaatacgta gtcgttgcaa gtccgcacca 11700 ggtactggta tcccaccaaa aagtgcggcg gcggctggcg gtagaggggc cagcgtaggg 11760 tggccggggc tccgggggcg agatcttcca acataaggcg atgatatccg tagatgtacc 11820 tggacatcca ggtgatgccg gcggcggtgg tggaggcgcg cggaaagtcg cggacgcggt 11880 tccagatgtt gcgcagcggc aaaaagtgct ccatggtcgg gacgctctgg ccggtcaggc 11940 gcgcgcaatc gttgacgctc tagcgtgcaa aaggagagcc tgtaagcggg cactcttccg 12000 tggtctggtg gataaattcg caagggtatc atggcggacg accggggttc gagccccgta 12060 tccggccgtc cgccgtgatc catgcggtta ccgcccgcgt gtcgaaccca ggtgtgcgac 12120 gtcagacaac gggggagtgc tccttttggc ttccttccag gcgcggcggc tgctgcgcta 12180 gcttttttgg ccactggccg cgcgcagcgt aagcggttag gctggaaagc gaaagcatta 12240 agtggctcgc tccctgtagc cggagggtta ttttccaagg gttgagtcgc gggacccccg 12300 gttcgagtct cggaccggcc ggactgcggc gaacgggggt ttgcctcccc gtcatgcaag 12360 accccgcttg caaattcctc cggaaacagg gacgagcccc ttttttgctt ttcccagatg 12420 catccggtgc tgcggcagat gcgcccccct cctcagcagc ggcaagagca agagcagcgg 12480 cagacatgca gggcaccctc ccctcctcct accgcgtcag gaggggcgac atccgcggtt 12540 gacgcggcag cagatggtga ttacgaaccc ccgcggcgcc gggcccggca ctacctggac 12600 ttggaggagg gcgagggcct ggcgcggcta ggagcgccct ctcctgagcg gcacccaagg 12660 gtgcagctga agcgtgatac gcgtgaggcg tacgtgccgc ggcagaacct gtttcgcgac 12720 cgcgagggag aggagcccga ggagatgcgg gatcgaaagt tccacgcagg gcgcgagctg 12780 cggcatggcc tgaatcgcga gcggttgctg cgcgaggagg actttgagcc cgacgcgcga 12840 accgggatta gtcccgcgcg cgcacacgtg gcggccgccg acctggtaac cgcatacgag 12900 cagacggtga accaggagat taactttcaa aaaagcttta acaaccacgt gcgtacgctt 12960 gtggcgcgcg aggaggtggc tataggactg atgcatctgt gggactttgt aagcgcgctg 13020 gagcaaaacc caaatagcaa gccgctcatg gcgcagctgt tccttatagt gcagcacagc 13080 agggacaacg aggcattcag ggatgcgctg ctaaacatag tagagcccga gggccgctgg 13140 ctgctcgatt tgataaacat cctgcagagc atagtggtgc aggagcgcag cttgagcctg 13200 gctgacaagg tggccgccat caactattcc atgcttagcc tgggcaagtt ttacgcccgc 13260 aagatatacc atacccctta cgttcccata gacaaggagg taaagatcga ggggttctac 13320 atgcgcatgg cgctgaaggt gcttaccttg agcgacgacc tgggcgttta tcgcaacgag 13380 cgcatccaca aggccgtgag cgtgagccgg cggcgcgagc tcagcgaccg cgagctgatg 13440 cacagcctgc aaagggccct ggctggcacg ggcagcggcg atagagaggc cgagtcctac 13500 tttgacgcgg gcgctgacct gcgctgggcc ccaagccgac gcgccctgga ggcagctggg 13560 gccggacctg ggctggcggt ggcacccgcg cgcgctggca acgtcggcgg cgtggaggaa 13620 tatgacgagg acgatgagta cgagccagag gacggcgagt actaagcggt gatgtttctg 13680 atcagatgat gcaagacgca acggacccgg cggtgcgggc ggcgctgcag agccagccgt 13740 ccggccttaa ctccacggac gactggcgcc aggtcatgga ccgcatcatg tcgctgactg 13800 cgcgcaatcc tgacgcgttc cggcagcagc cgcaggccaa ccggctctcc gcaattctgg 13860 aagcggtggt cccggcgcgc gcaaacccca cgcacgagaa ggtgctggcg atcgtaaacg 13920 cgctggccga aaacagggcc atccggcccg acgaggccgg cctggtctac gacgcgctgc 13980 ttcagcgcgt ggctcgttac aacagcggca acgtgcagac caacctggac cggctggtgg 14040

gggatgtgcg cgaggccgtg gcgcagcgtg agcgcgcgca gcagcagggc aacctgggct 14100 ccatggttgc actaaacgcc ttcctgagta cacagcccgc caacgtgccg cggggacagg 14160 aggactacac caactttgtg agcgcactgc ggctaatggt gactgagaca ccgcaaagtg 14220 aggtgtacca gtctgggcca gactattttt tccagaccag tagacaaggc ctgcagaccg 14280 taaacctgag ccaggctttc aaaaacttgc aggggctgtg gggggtgcgg gctcccacag 14340 gcgaccgcgc gaccgtgtct agcttgctga cgcccaactc gcgcctgttg ctgctgctaa 14400 tagcgccctt cacggacagt ggcagcgtgt cccgggacac atacctaggt cacttgctga 14460 cactgtaccg cgaggccata ggtcaggcgc atgtggacga gcatactttc caggagatta 14520 caagtgtcag ccgcgcgctg gggcaggagg acacgggcag cctggaggca accctaaact 14580 acctgctgac caaccggcgg cagaagatcc cctcgttgca cagtttaaac agcgaggagg 14640 agcgcatttt gcgctacgtg cagcagagcg tgagccttaa cctgatgcgc gacggggtaa 14700 cgcccagcgt ggcgctggac atgaccgcgc gcaacatgga accgggcatg tatgcctcaa 14760 accggccgtt tatcaaccgc ctaatggact acttgcatcg cgcggccgcc gtgaaccccg 14820 agtatttcac caatgccatc ttgaacccgc actggctacc gccccctggt ttctacaccg 14880 ggggattcga ggtgcccgag ggtaacgatg gattcctctg ggacgacata gacgacagcg 14940 tgttttcccc gcaaccgcag accctgctag agttgcaaca gcgcgagcag gcagaggcgg 15000 cgctgcgaaa ggaaagcttc cgcaggccaa gcagcttgtc cgatctaggc gctgcggccc 15060 cgcggtcaga tgctagtagc ccatttccaa gcttgatagg gtctcttacc agcactcgca 15120 ccacccgccc gcgcctgctg ggcgaggagg agtacctaaa caactcgctg ctgcagccgc 15180 agcgcgaaaa aaacctgcct ccggcatttc ccaacaacgg gatagagagc ctagtggaca 15240 agatgagtag atggaagacg tacgcgcagg agcacaggga cgtgccaggc ccgcgcccgc 15300 ccacccgtcg tcaaaggcac gaccgtcagc ggggtctggt gtgggaggac gatgactcgg 15360 cagacgacag cagcgtcctg gatttgggag ggagtggcaa cccgtttgcg caccttcgcc 15420 ccaggctggg gagaatgttt taaaaaaaaa aaagcatgat gcaaaataaa aaactcacca 15480 aggccatggc accgagcgtt ggttttcttg tattcccctt agtatgcggc gcgcggcgat 15540 gtatgaggaa ggtcctcctc cctcctacga gagtgtggtg agcgcggcgc cagtggcggc 15600 ggcgctgggt tctcccttcg atgctcccct ggacccgccg tttgtgcctc cgcggtacct 15660 gcggcctacc ggggggagaa acagcatccg ttactctgag ttggcacccc tattcgacac 15720 cacccgtgtg tacctggtgg acaacaagtc aacggatgtg gcatccctga actaccagaa 15780 cgaccacagc aactttctga ccacggtcat tcaaaacaat gactacagcc cgggggaggc 15840 aagcacacag accatcaatc ttgacgaccg gtcgcactgg ggcggcgacc tgaaaaccat 15900 cctgcatacc aacatgccaa atgtgaacga gttcatgttt accaataagt ttaaggcgcg 15960 ggtgatggtg tcgcgcttgc ctactaagga caatcaggtg gagctgaaat acgagtgggt 16020 ggagttcacg ctgcccgagg gcaactactc cgagaccatg accatagacc ttatgaacaa 16080 cgcgatcgtg gagcactact tgaaagtggg cagacagaac ggggttctgg aaagcgacat 16140 cggggtaaag tttgacaccc gcaacttcag actggggttt gaccccgtca ctggtcttgt 16200 catgcctggg gtatatacaa acgaagcctt ccatccagac atcattttgc tgccaggatg 16260 cggggtggac ttcacccaca gccgcctgag caacttgttg ggcatccgca agcggcaacc 16320 cttccaggag ggctttagga tcacctacga tgatctggag ggtggtaaca ttcccgcact 16380 gttggatgtg gacgcctacc aggcgagctt gaaagatgac accgaacagg gcgggggtgg 16440 cgcaggcggc agcaacagca gtggcagcgg cgcggaagag aactccaacg cggcagccgc 16500 ggcaatgcag ccggtggagg acatgaacga tcatgccatt cgcggcgaca cctttgccac 16560 acgggctgag gagaagcgcg ctgaggccga agcagcggcc gaagctgccg cccccgctgc 16620 gcaacccgag gtcgagaagc ctcagaagaa accggtgatc aaacccctga cagaggacag 16680 caagaaacgc agttacaacc taataagcaa tgacagcacc ttcacccagt accgcagctg 16740 gtaccttgca tacaactacg gcgaccctca gaccggaatc cgctcatgga ccctgctttg 16800 cactcctgac gtaacctgcg gctcggagca ggtctactgg tcgttgccag acatgatgca 16860 agaccccgtg accttccgct ccacgcgcca gatcagcaac tttccggtgg tgggcgccga 16920 gctgttgccc gtgcactcca agagcttcta caacgaccag gccgtctact cccaactcat 16980 ccgccagttt acctctctga cccacgtgtt caatcgcttt cccgagaacc agattttggc 17040 gcgcccgcca gcccccacca tcaccaccgt cagtgaaaac gttcctgctc tcacagatca 17100 cgggacgcta ccgctgcgca acagcatcgg aggagtccag cgagtgacca ttactgacgc 17160 cagacgccgc acctgcccct acgtttacaa ggccctgggc atagtctcgc cgcgcgtcct 17220 atcgagccgc actttttgag caagcatgtc catccttata tcgcccagca ataacacagg 17280 ctggggcctg cgcttcccaa gcaagatgtt tggcggggcc aagaagcgct ccgaccaaca 17340 cccagtgcgc gtgcgcgggc actaccgcgc gccctggggc gcgcacaaac gcggccgcac 17400 tgggcgcacc accgtcgatg acgccatcga cgcggtggtg gaggaggcgc gcaactacac 17460 gcccacgccg ccaccagtgt ccacagtgga cgcggccatt cagaccgtgg tgcgcggagc 17520 ccggcgctat gctaaaatga agagacggcg gaggcgcgta gcacgtcgcc accgccgccg 17580 acccggcact gccgcccaac gcgcggcggc ggccctgctt aaccgcgcac gtcgcaccgg 17640 ccgacgggcg gccatgcggg ccgctcgaag gctggccgcg ggtattgtca ctgtgccccc 17700 caggtccagg cgacgagcgg ccgccgcagc agccgcggcc attagtgcta tgactcaggg 17760 tcgcaggggc aacgtgtatt gggtgcgcga ctcggttagc ggcctgcgcg tgcccgtgcg 17820 cacccgcccc ccgcgcaact agattgcaag aaaaaactac ttagactcgt actgttgtat 17880 gtatccagcg gcggcggcgc gcaacgaagc tatgtccaag cgcaaaatca aagaagagat 17940 gctccaggtc atcgcgccgg agatctatgg ccccccgaag aaggaagagc aggattacaa 18000 gccccgaaag ctaaagcggg tcaaaaagaa aaagaaagat gatgatgatg aacttgacga 18060 cgaggtggaa ctgctgcacg ctaccgcgcc caggcgacgg gtacagtgga aaggtcgacg 18120 cgtaaaacgt gttttgcgac ccggcaccac cgtagtcttt acgcccggtg agcgctccac 18180 ccgcacctac aagcgcgtgt atgatgaggt gtacggcgac gaggacctgc ttgagcaggc 18240 caacgagcgc ctcggggagt ttgcctacgg aaagcggcat aaggacatgc tggcgttgcc 18300 gctggacgag ggcaacccaa cacctagcct aaagcccgta acactgcagc aggtgctgcc 18360 cgcgcttgca ccgtccgaag aaaagcgcgg cctaaagcgc gagtctggtg acttggcacc 18420 caccgtgcag ctgatggtac ccaagcgcca gcgactggaa gatgtcttgg aaaaaatgac 18480 cgtggaacct gggctggagc ccgaggtccg cgtgcggcca atcaagcagg tggcgccggg 18540 actgggcgtg cagaccgtgg acgttcagat acccactacc agtagcacca gtattgccac 18600 cgccacagag ggcatggaga cacaaacgtc cccggttgcc tcagcggtgg cggatgccgc 18660 ggtgcaggcg gtcgctgcgg ccgcgtccaa gacctctacg gaggtgcaaa cggacccgtg 18720 gatgtttcgc gtttcagccc cccggcgccc gcgccgttcg aggaagtacg gcgccgccag 18780 cgcgctactg cccgaatatg ccctacatcc ttccattgcg cctacccccg gctatcgtgg 18840 ctacacctac cgccccagaa gacgagcaac tacccgacgc cgaaccacca ctggaacccg 18900 ccgccgccgt cgccgtcgcc agcccgtgct ggccccgatt tccgtgcgca gggtggctcg 18960 cgaaggaggc aggaccctgg tgctgccaac agcgcgctac caccccagca tcgtttaaaa 19020 gccggtcttt gtggttcttg cagatatggc cctcacctgc cgcctccgtt tcccggtgcc 19080 gggattccga ggaagaatgc accgtaggag gggcatggcc ggccacggcc tgacgggcgg 19140 catgcgtcgt gcgcaccacc ggcggcggcg cgcgtcgcac cgtcgcatgc gcggcggtat 19200 cctgcccctc cttattccac tgatcgccgc ggcgattggc gccgtgcccg gaattgcatc 19260 cgtggccttg caggcgcaga gacactgatt aaaaacaagt tgcatgtgga aaaatcaaaa 19320 taaaaagtct ggactctcac gctcgcttgg tcctgtaact attttgtaga atggaagaca 19380 tcaactttgc gtctctggcc ccgcgacacg gctcgcgccc gttcatggga aactggcaag 19440 atatcggcac cagcaatatg agcggtggcg ccttcagctg gggctcgctg tggagcggca 19500 ttaaaaattt cggttccacc gttaagaact atggcagcaa ggcctggaac agcagcacag 19560 gccagatgct gagggataag ttgaaagagc aaaatttcca acaaaaggtg gtagatggcc 19620 tggcctctgg cattagcggg gtggtggacc tggccaacca ggcagtgcaa aataagatta 19680 acagtaagct tgatccccgc cctcccgtag aggagcctcc accggccgtg gagacagtgt 19740 ctccagaggg gcgtggcgaa aagcgtccgc gccccgacag ggaagaaact ctggtgacgc 19800 aaatagacga gcctccctcg tacgaggagg cactaaagca aggcctgccc accacccgtc 19860 ccatcgcgcc catggctacc ggagtgctgg gccagcacac acccgtaacg ctggacctgc 19920 ctccccccgc cgacacccag cagaaacctg tgctgccagg cccgaccgcc gttgttgtaa 19980 cccgtcctag ccgcgcgtcc ctgcgccgcg ccgccagcgg tccgcgatcg ttgcggcccg 20040 tagccagtgg caactggcaa agcacactga acagcatcgt gggtctgggg gtgcaatccc 20100 tgaagcgccg acgatgcttc tgatagctaa cgtgtcgtat gtgtgtcatg tatgcgtcca 20160 tgtcgccgcc agaggagctg ctgagccgcc gcgcgcccgc tttccaagat ggctacccct 20220 tcgatgatgc cgcagtggtc ttacatgcac atctcgggcc aggacgcctc ggagtacctg 20280 agccccgggc tggtgcagtt tgcccgcgcc accgagacgt acttcagcct gaataacaag 20340 tttagaaacc ccacggtggc gcctacgcac gacgtgacca cagaccggtc ccagcgtttg 20400 acgctgcggt tcatccctgt ggaccgtgag gatactgcgt actcgtacaa ggcgcggttc 20460 accctagctg tgggtgataa ccgtgtgctg gacatggctt ccacgtactt tgacatccgc 20520 ggcgtgctgg acaggggccc tacttttaag ccctactctg gcactgccta caacgccctg 20580 gctcccaagg gtgccccaaa tccttgcgaa tgggatgaag ctgctactgc tcttgaaata 20640 aacctagaag aagaggacga tgacaacgaa gacgaagtag acgagcaagc tgagcagcaa 20700 aaaactcacg tatttgggca ggcgccttat tctggtataa atattacaaa ggagggtatt 20760 caaataggtg tcgaaggtca aacacctaaa tatgccgata aaacatttca acctgaacct 20820 caaataggag aatctcagtg gtacgaaaca gaaattaatc atgcagctgg gagagtccta 20880 aaaaagacta ccccaatgaa accatgttac ggttcatatg caaaacccac aaatgaaaat 20940 ggagggcaag gcattcttgt aaagcaacaa aatggaaagc tagaaagtca agtggaaatg 21000 caatttttct caactactga ggcagccgca ggcaatggtg ataacttgac tcctaaagtg 21060 gtattgtaca gtgaagatgt agatatagaa accccagaca ctcatatttc ttacatgccc 21120 actattaagg aaggtaactc acgagaacta atgggccaac aatctatgcc caacaggcct 21180 aattacattg cttttaggga caattttatt ggtctaatgt attacaacag cacgggtaat 21240 atgggtgttc tggcgggcca agcatcgcag ttgaatgctg ttgtagattt gcaagacaga 21300 aacacagagc tttcatacca gcttttgctt gattccattg gtgatagaac caggtacttt 21360 tctatgtgga atcaggctgt tgacagctat gatccagatg ttagaattat tgaaaatcat 21420 ggaactgaag atgaacttcc aaattactgc tttccactgg gaggtgtgat taatacagag 21480 actcttacca aggtaaaacc taaaacaggt caggaaaatg gatgggaaaa agatgctaca 21540

gaattttcag ataaaaatga aataagagtt ggaaataatt ttgccatgga aatcaatcta 21600 aatgccaacc tgtggagaaa tttcctgtac tccaacatag cgctgtattt gcccgacaag 21660 ctaaagtaca gtccttccaa cgtaaaaatt tctgataacc caaacaccta cgactacatg 21720 aacaagcgag tggtggctcc cgggctagtg gactgctaca ttaaccttgg agcacgctgg 21780 tcccttgact atatggacaa cgtcaaccca tttaaccacc accgcaatgc tggcctgcgc 21840 taccgctcaa tgttgctggg caatggtcgc tatgtgccct tccacatcca ggtgcctcag 21900 aagttctttg ccattaaaaa cctccttctc ctgccgggct catacaccta cgagtggaac 21960 ttcaggaagg atgttaacat ggttctgcag agctccctag gaaatgacct aagggttgac 22020 ggagccagca ttaagtttga tagcatttgc ctttacgcca ccttcttccc catggcccac 22080 aacaccgcct ccacgcttga ggccatgctt agaaacgaca ccaacgacca gtcctttaac 22140 gactatctct ccgccgccaa catgctctac cctatacccg ccaacgctac caacgtgccc 22200 atatccatcc cctcccgcaa ctgggcggct ttccgcggct gggccttcac gcgccttaag 22260 actaaggaaa ccccatcact gggctcgggc tacgaccctt attacaccta ctctggctct 22320 ataccctacc tagatggaac cttttacctc aaccacacct ttaagaaggt ggccattacc 22380 tttgactctt ctgtcagctg gcctggcaat gaccgcctgc ttacccccaa cgagtttgaa 22440 attaagcgct cagttgacgg ggagggttac aacgttgccc agtgtaacat gaccaaagac 22500 tggttcctgg tacaaatgct agctaactat aacattggct accagggctt ctatatccca 22560 gagagctaca aggaccgcat gtactccttc tttagaaact tccagcccat gagccgtcag 22620 gtggtggatg atactaaata caaggactac caacaggtgg gcatcctaca ccaacacaac 22680 aactctggat ttgttggcta ccttgccccc accatgcgcg aaggacaggc ctaccctgct 22740 aacttcccct atccgcttat aggcaagacc gcagttgaca gcattaccca gaaaaagttt 22800 ctttgcgatc gcaccctttg gcgcatccca ttctccagta actttatgtc catgggcgca 22860 ctcacagacc tgggccaaaa ccttctctac gccaactccg cccacgcgct agacatgact 22920 tttgaggtgg atcccatgga cgagcccacc cttctttatg ttttgtttga agtctttgac 22980 gtggtccgtg tgcaccagcc gcaccgcggc gtcatcgaaa ccgtgtacct gcgcacgccc 23040 ttctcggccg gcaacgccac aacataaaga agcaagcaac atcaacaaca gctgccgcca 23100 tgggctccag tgagcaggaa ctgaaagcca ttgtcaaaga tcttggttgt gggccatatt 23160 ttttgggcac ctatgacaag cgctttccag gctttgtttc tccacacaag ctcgcctgcg 23220 ccatagtcaa tacggccggt cgcgagactg ggggcgtaca ctggatggcc tttgcctgga 23280 acccgcactc aaaaacatgc tacctctttg agccctttgg cttttctgac cagcgactca 23340 agcaggttta ccagtttgag tacgagtcac tcctgcgccg tagcgccatt gcttcttccc 23400 ccgaccgctg tataacgctg gaaaagtcca cccaaagcgt acaggggccc aactcggccg 23460 cctgtggact attctgctgc atgtttctcc acgcctttgc caactggccc caaactccca 23520 tggatcacaa ccccaccatg aaccttatta ccggggtacc caactccatg ctcaacagtc 23580 cccaggtaca gcccaccctg cgtcgcaacc aggaacagct ctacagcttc ctggagcgcc 23640 actcgcccta cttccgcagc cacagtgcgc agattaggag cgccacttct ttttgtcact 23700 tgaaaaacat gtaaaaataa tgtactagag acactttcaa taaaggcaaa tgcttttatt 23760 tgtacactct cgggtgatta tttaccccca cccttgccgt ctgcgccgtt taaaaatcaa 23820 aggggttctg ccgcgcatcg ctatgcgcca ctggcaggga cacgttgcga tactggtgtt 23880 tagtgctcca cttaaactca ggcacaacca tccgcggcag ctcggtgaag ttttcactcc 23940 acaggctgcg caccatcacc aacgcgttta gcaggtcggg cgccgatatc ttgaagtcgc 24000 agttggggcc tccgccctgc gcgcgcgagt tgcgatacac agggttgcag cactggaaca 24060 ctatcagcgc cgggtggtgc acgctggcca gcacgctctt gtcggagatc agatccgcgt 24120 ccaggtcctc cgcgttgctc agggcgaacg gagtcaactt tggtagctgc cttcccaaaa 24180 agggcgcgtg cccaggcttt gagttgcact cgcaccgtag tggcatcaaa aggtgaccgt 24240 gcccggtctg ggcgttagga tacagcgcct gcataaaagc cttgatctgc ttaaaagcca 24300 cctgagcctt tgcgccttca gagaagaaca tgccgcaaga cttgccggaa aactgattgg 24360 ccggacaggc cgcgtcgtgc acgcagcacc ttgcgtcggt gttggagatc tgcaccacat 24420 ttcggcccca ccggttcttc acgatcttgg ccttgctaga ctgctccttc agcgcgcgct 24480 gcccgttttc gctcgtcaca tccatttcaa tcacgtgctc cttatttatc ataatgcttc 24540 cgtgtagaca cttaagctcg ccttcgatct cagcgcagcg gtgcagccac aacgcgcagc 24600 ccgtgggctc gtgatgcttg taggtcacct ctgcaaacga ctgcaggtac gcctgcagga 24660 atcgccccat catcgtcaca aaggtcttgt tgctggtgaa ggtcagctgc aacccgcggt 24720 gctcctcgtt cagccaggtc ttgcatacgg ccgccagagc ttccacttgg tcaggcagta 24780 gtttgaagtt cgcctttaga tcgttatcca cgtggtactt gtccatcagc gcgcgcgcag 24840 cctccatgcc cttctcccac gcagacacga tcggcacact cagcgggttc atcaccgtaa 24900 tttcactttc cgcttcgctg ggctcttcct cttcctcttg cgtccgcata ccacgcgcca 24960 ctgggtcgtc ttcattcagc cgccgcactg tgcgcttacc tcctttgcca tgcttgatta 25020 gcaccggtgg gttgctgaaa cccaccattt gtagcgccac atcttctctt tcttcctcgc 25080 tgtccacgat tacctctggt gatggcgggc gctcgggctt gggagaaggg cgcttctttt 25140 tcttcttggg cgcaatggcc aaatccgccg ccgaggtcga tggccgcggg ctgggtgtgc 25200 gcggcaccag cgcgtcttgt gatgagtctt cctcgtcctc ggactcgata cgccgcctca 25260 tccgcttttt tgggggcgcc cggggaggcg gcggcgacgg ggacggggac gacacgtcct 25320 ccatggttgg gggacgtcgc gccgcaccgc gtccgcgctc gggggtggtt tcgcgctgct 25380 cctcttcccg actggccatt tccttctcct ataggcagaa aaagatcatg gagtcagtcg 25440 agaagaagga cagcctaacc gccccctctg agttcgccac caccgcctcc accgatgccg 25500 ccaacgcgcc taccaccttc cccgtcgagg cacccccgct tgaggaggag gaagtgatta 25560 tcgagcagga cccaggtttt gtaagcgaag acgacgagga ccgctcagta ccaacagagg 25620 ataaaaagca agaccaggac aacgcagagg caaacgagga acaagtcggg cggggggacg 25680 aaaggcatgg cgactaccta gatgtgggag acgacgtgct gttgaagcat ctgcagcgcc 25740 agtgcgccat tatctgcgac gcgttgcaag agcgcagcga tgtgcccctc gccatagcgg 25800 atgtcagcct tgcctacgaa cgccacctat tctcaccgcg cgtacccccc aaacgccaag 25860 aaaacggcac atgcgagccc aacccgcgcc tcaacttcta ccccgtattt gccgtgccag 25920 aggtgcttgc cacctatcac atctttttcc aaaactgcaa gataccccta tcctgccgtg 25980 ccaaccgcag ccgagcggac aagcagctgg ccttgcggca gggcgctgtc atacctgata 26040 tcgcctcgct caacgaagtg ccaaaaatct ttgagggtct tggacgcgac gagaagcgcg 26100 cggcaaacgc tctgcaacag gaaaacagcg aaaatgaaag tcactctgga gtgttggtgg 26160 aactcgaggg tgacaacgcg cgcctagccg tactaaaacg cagcatcgag gtcacccact 26220 ttgcctaccc ggcacttaac ctacccccca aggtcatgag cacagtcatg agtgagctga 26280 tcgtgcgccg tgcgcagccc ctggagaggg atgcaaattt gcaagaacaa acagaggagg 26340 gcctacccgc agttggcgac gagcagctag cgcgctggct tcaaacgcgc gagcctgccg 26400 acttggagga gcgacgcaaa ctaatgatgg ccgcagtgct cgttaccgtg gagcttgagt 26460 gcatgcagcg gttctttgct gacccggaga tgcagcgcaa gctagaggaa acattgcact 26520 acacctttcg acagggctac gtacgccagg cctgcaagat ctccaacgtg gagctctgca 26580 acctggtctc ctaccttgga attttgcacg aaaaccgcct tgggcaaaac gtgcttcatt 26640 ccacgctcaa gggcgaggcg cgccgcgact acgtccgcga ctgcgtttac ttatttctat 26700 gctacacctg gcagacggcc atgggcgttt ggcagcagtg cttggaggag tgcaacctca 26760 aggagctgca gaaactgcta aagcaaaact tgaaggacct atggacggcc ttcaacgagc 26820 gctccgtggc cgcgcacctg gcggacatca ttttccccga acgcctgctt aaaaccctgc 26880 aacagggtct gccagacttc accagtcaaa gcatgttgca gaactttagg aactttatcc 26940 tagagcgctc aggaatcttg cccgccacct gctgtgcact tcctagcgac tttgtgccca 27000 ttaagtaccg cgaatgccct ccgccgcttt ggggccactg ctaccttctg cagctagcca 27060 actaccttgc ctaccactct gacataatgg aagacgtgag cggtgacggt ctactggagt 27120 gtcactgtcg ctgcaaccta tgcaccccgc accgctccct ggtttgcaat tcgcagctgc 27180 ttaacgaaag tcaaattatc ggtacctttg agctgcaggg tccctcgcct gacgaaaagt 27240 ccgcggctcc ggggttgaaa ctcactccgg ggctgtggac gtcggcttac cttcgcaaat 27300 ttgtacctga ggactaccac gcccacgaga ttaggttcta cgaagaccaa tcccgcccgc 27360 ctaatgcgga gcttaccgcc tgcgtcatta cccagggcca cattcttggc caattgcaag 27420 ccatcaacaa agcccgccaa gagtttctgc tacgaaaggg acggggggtt tacttggacc 27480 cccagtccgg cgaggagctc aacccaatcc ccccgccgcc gcagccctat cagcagcagc 27540 cgcgggccct tgcttcccag gatggcaccc aaaaagaagc tgcagctgcc gccgccaccc 27600 acggacgagg aggaatactg ggacagtcag gcagaggagg ttttggacga ggaggaggag 27660 gacatgatgg aagactggga gagcctagac gaggaagctt ccgaggtcga agaggtgtca 27720 gacgaaacac cgtcaccctc ggtcgcattc ccctcgccgg cgccccagaa atcggcaacc 27780 ggttccagca tggctacaac ctccgctcct caggcgccgc cggcactgcc cgttcgccga 27840 cccaaccgta gatgggacac cactggaacc agggccggta agtccaagca gccgccgccg 27900 ttagcccaag agcaacaaca gcgccaaggc taccgctcat ggcgcgggca caagaacgcc 27960 atagttgctt gcttgcaaga ctgtgggggc aacatctcct tcgcccgccg ctttcttctc 28020 taccatcacg gcgtggcctt cccccgtaac atcctgcatt actaccgtca tctctacagc 28080 ccatactgca ccggcggcag cggcagcaac agcagcggcc acacagaagc aaaggcgacc 28140 ggatagcaag actctgacaa agcccaagaa atccacagcg gcggcagcag caggaggagg 28200 agcgctgcgt ctggcgccca acgaacccgt atcgacccgc gagcttagaa acaggatttt 28260 tcccactctg tatgctatat ttcaacagag caggggccaa gaacaagagc tgaaaataaa 28320 aaacaggtct ctgcgatccc tcacccgcag ctgcctgtat cacaaaagcg aagatcagct 28380 tcggcgcacg ctggaagacg cggaggctct cttcagtaaa tactgcgcgc tgactcttaa 28440 ggactagttt cgcgcccttt ctcaaattta agcgcgaaaa ctacgtcatc tccagcggcc 28500 acacccggcg ccagcacctg ttgtcagcgc cattatgagc aaggaaattc ccacgcccta 28560 catgtggagt taccagccac aaatgggact tgcggctgga gctgcccaag actactcaac 28620 ccgaataaac tacatgagcg cgggacccca catgatatcc cgggtcaacg gaatacgcgc 28680 ccaccgaaac cgaattctcc tggaacaggc ggctattacc accacacctc gtaataacct 28740 taatccccgt agttggcccg ctgccctggt gtaccaggaa agtcccgctc ccaccactgt 28800 ggtacttccc agagacgccc aggccgaagt tcagatgact aactcagggg cgcagcttgc 28860 gggcggcttt cgtcacaggg tgcggtcgcc cgggcagggt ataactcacc tgacaatcag 28920 agggcgaggt attcagctca acgacgagtc ggtgagctcc tcgcttggtc tccgtccgga 28980 cgggacattt cagatcggcg gcgccggccg ctcttcattc acgcctcgtc aggcaatcct 29040 aactctgcag acctcgtcct ctgagccgcg ctctggaggc attggaactc tgcaatttat 29100

tgaggagttt gtgccatcgg tctactttaa ccccttctcg ggacctcccg gccactatcc 29160 ggatcaattt attcctaact ttgacgcggt aaaggactcg gcggacggct acgactgaat 29220 gttaagtgga gaggcagagc aactgcgcct gaaacacctg gtccactgtc gccgccacaa 29280 gtgctttgcc cgcgactccg gtgagttttg ctactttgaa ttgcccgagg atcatatcga 29340 gggcccggcg cacggcgtcc ggcttaccgc ccagggagag cttgcccgta gcctgattcg 29400 ggagtttacc cagcgccccc tgctagttga gcgggacagg ggaccctgtg ttctcactgt 29460 gatttgcaac tgtcctaacc ctggattaca tcaagatcct ctagttaatg tcaggtcgcc 29520 taagtcgatt aactagagta cccggggatc ttattccctt taactaataa aaaaaaataa 29580 taaagcatca cttacttaaa atcagttagc aaatttctgt ccagtttatt cagcagcacc 29640 tccttgccct cctcccagct ctggtattgc agcttcctcc tggctgcaaa ctttctccac 29700 aatctaaatg gaatgtcagt ttcctcctgt tcctgtccat ccgcacccac tatcttcatg 29760 ttgttgcaga tgaagcgcgc aagaccgtct gaagatacct tcaaccccgt gtatccatat 29820 gacacggaaa ccggtcctcc aactgtgcct tttcttactc ctccctttgt atcccccaat 29880 gggtttcaag agagtccccc tggggtactc tctttgcgcc tatccgaacc tctagttacc 29940 tccaatggca tgcttgcgct caaaatgggc aacggcctct ctctggacga ggccggcaac 30000 cttacctccc aaaatgtaac cactgtgagc ccacctctca aaaaaaccaa gtcaaacata 30060 aacctggaaa tatctgcacc cctcacagtt acctcagaag ccctaactgt ggctgccgcc 30120 gcacctctaa tggtcgcggg caacacactc accatgcaat cacaggcccc gctaaccgtg 30180 cacgactcca aacttagcat tgccacccaa ggacccctca cagtgtcaga aggaaagcta 30240 gccctgcaaa catcaggccc cctcaccacc accgatagca gtacccttac tatcactgcc 30300 tcaccccctc taactactgc cactggtagc ttgggcattg acttgaaaga gcccatttat 30360 acacaaaatg gaaaactagg actaaagtac ggggctcctt tgcatgtaac agacgaccta 30420 aacactttga ccgtagcaac tggtccaggt gtgactatta ataatacttc cttgcaaact 30480 aaagttactg gagccttggg ttttgattca caaggcaata tgcaacttaa tgtagcagga 30540 ggactaagga ttgattctca aaacagacgc cttatacttg atgttagtta tccgtttgat 30600 gctcaaaacc aactaaatct aagactagga cagggccctc tttttataaa ctcagcccac 30660 aacttggata ttaactacaa caaaggcctt tacttgttta cagcttcaaa caattccaaa 30720 aagcttgagg ttaacctaag cactgccaag gggttgatgt ttgacgctac agccatagcc 30780 attaatgcag gagatgggct tgaatttggt tcacctaatg caccaaacac aaatcccctc 30840 aaaacaaaaa ttggccatgg cctagaattt gattcaaaca aggctatggt tcctaaacta 30900 ggaactggcc ttagttttga cagcacaggt gccattacag taggaaacaa aaataatgat 30960 aagctaactt tgtggaccac accagctcca tctcctaact gtagactaaa tgcagagaaa 31020 gatgctaaac tcactttggt cttaacaaaa tgtggcagtc aaatacttgc tacagtttca 31080 gttttggctg ttaaaggcag tttggctcca atatctggaa cagttcaaag tgctcatctt 31140 attataagat ttgacgaaaa tggagtgcta ctaaacaatt ccttcctgga cccagaatat 31200 tggaacttta gaaatggaga tcttactgaa ggcacagcct atacaaacgc tgttggattt 31260 atgcctaacc tatcagctta tccaaaatct cacggtaaaa ctgccaaaag taacattgtc 31320 agtcaagttt acttaaacgg agacaaaact aaacctgtaa cactaaccat tacactaaac 31380 ggtacacagg aaacaggaga cacaactcca agtgcatact ctatgtcatt ttcatgggac 31440 tggtctggcc acaactacat taatgaaata tttgccacat cctcttacac tttttcatac 31500 attgcccaag aataaagaat cgtttgtgtt atgtttcaac gtgtttattt ttcaattgca 31560 gaaaatttca agtcattttt cattcagtag tatagcccca ccaccacata gcttatacag 31620 atcaccgtac cttaatcaaa ctcacagaac cctagtattc aacctgccac ctccctccca 31680 acacacagag tacacagtcc tttctccccg gctggcctta aaaagcatca tatcatgggt 31740 aacagacata ttcttaggtg ttatattcca cacggtttcc tgtcgagcca aacgctcatc 31800 agtgatatta ataaactccc cgggcagctc acttaagttc atgtcgctgt ccagctgctg 31860 agccacaggc tgctgtccaa cttgcggttg cttaacgggc ggcgaaggag aagtccacgc 31920 ctacatgggg gtagagtcat aatcgtgcat caggataggg cggtggtgct gcagcagcgc 31980 gcgaataaac tgctgccgcc gccgctccgt cctgcaggaa tacaacatgg cagtggtctc 32040 ctcagcgatg attcgcaccg cccgcagcat aaggcgcctt gtcctccggg cacagcagcg 32100 caccctgatc tcacttaaat cagcacagta actgcagcac agcaccacaa tattgttcaa 32160 aatcccacag tgcaaggcgc tgtatccaaa gctcatggcg gggaccacag aacccacgtg 32220 gccatcatac cacaagcgca ggtagattaa gtggcgaccc ctcataaaca cgctggacat 32280 aaacattacc tcttttggca tgttgtaatt caccacctcc cggtaccata taaacctctg 32340 attaaacatg gcgccatcca ccaccatcct aaaccagctg gccaaaacct gcccgccggc 32400 tatacactgc agggaaccgg gactggaaca atgacagtgg agagcccagg actcgtaacc 32460 atggatcatc atgctcgtca tgatatcaat gttggcacaa cacaggcaca cgtgcataca 32520 cttcctcagg attacaagct cctcccgcgt tagaaccata tcccagggaa caacccattc 32580 ctgaatcagc gtaaatccca cactgcaggg aagacctcgc acgtaactca cgttgtgcat 32640 tgtcaaagtg ttacattcgg gcagcagcgg atgatcctcc agtatggtag cgcgggtttc 32700 tgtctcaaaa ggaggtagac gatccctact gtacggagtg cgccgagaca accgagatcg 32760 tgttggtcgt agtgtcatgc caaatggaac gccggacgta gtcatatttc ctgaagcaaa 32820 accaggtgcg ggcgtgacaa acagatctgc gtctccggtc tcgccgctta gatcgctctg 32880 tgtagtagtt gtagtatatc cactctctca aagcatccag gcgccccctg gcttcgggtt 32940 ctatgtaaac tccttcatgc gccgctgccc tgataacatc caccaccgca gaataagcca 33000 cacccagcca acctacacat tcgttctgcg agtcacacac gggaggagcg ggaagagctg 33060 gaagaaccat gttttttttt ttattccaaa agattatcca aaacctcaaa atgaagatct 33120 attaagtgaa cgcgctcccc tccggtggcg tggtcaaact ctacagccaa agaacagata 33180 atggcatttg taagatgttg cacaatggct tccaaaaggc aaacggccct cacgtccaag 33240 tggacgtaaa ggctaaaccc ttcagggtga atctcctcta taaacattcc agcaccttca 33300 accatgccca aataattctc atctcgccac cttctcaata tatctctaag caaatcccga 33360 atattaagtc cggccattgt aaaaatctgc tccagagcgc cctccacctt cagcctcaag 33420 cagcgaatca tgattgcaaa aattcaggtt cctcacagac ctgtataaga ttcaaaagcg 33480 gaacattaac aaaaataccg cgatcccgta ggtcccttcg cagggccagc tgaacataat 33540 cgtgcaggtc tgcacggacc agcgcggcca cttccccgcc aggaaccatg acaaaagaac 33600 ccacactgat tatgacacgc atactcggag ctatgctaac cagcgtagcc ccgatgtaag 33660 cttgttgcat gggcggcgat ataaaatgca aggtgctgct caaaaaatca ggcaaagcct 33720 cgcgcaaaaa agaaagcaca tcgtagtcat gctcatgcag ataaaggcag gtaagctccg 33780 gaaccaccac agaaaaagac accatttttc tctcaaacat gtctgcgggt ttctgcataa 33840 acacaaaata aaataacaaa aaaacattta aacattagaa gcctgtctta caacaggaaa 33900 aacaaccctt ataagcataa gacggactac ggccatgccg gcgtgaccgt aaaaaaactg 33960 gtcaccgtga ttaaaaagca ccaccgacag ctcctcggtc atgtccggag tcataatgta 34020 agactcggta aacacatcag gttgattcac atcggtcagt gctaaaaagc gaccgaaata 34080 gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca taggaggtat 34140 aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct gcctaggcaa 34200 aatagcaccc tcccgctcca gaacaacata cagcgcttcc acagcggcag ccataacagt 34260 cagccttacc agtaaaaaag aaaacctatt aaaaaaacac cactcgacac ggcaccagct 34320 caatcagtca cagtgtaaaa aagggccaag tgcagagcga gtatatatag gactaaaaaa 34380 tgacgtaacg gttaaagtcc acaaaaaaca cccagaaaac cgcacgcgaa cctacgccca 34440 gaaacgaaag ccaaaaaacc cacaacttcc tcaaatcgtc acttccgttt tcccacgtta 34500 cgtcacttcc cattttaaga aaactacaat tcccaacaca tacaagttac tccgccctaa 34560 aacctacgtc acccgccccg ttcccacgcc ccgcgccacg tcacaaactc caccccctca 34620 ttatcatatt ggcttcaatc caaaataagg tatattattg atgat 34665 <210> SEQ ID NO 96 <211> LENGTH: 1644 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96 gtcgacgcca ccatgtgtca ccagcagctc gtgattagct ggttcagcct ggtgtttctg 60 gctagccctc tggtggccat ctgggagctg aagaaggacg tgtacgtggt ggagctcgac 120 tggtaccctg acgctcccgg cgagatggtc gtgctgacct gcgacacccc tgaggaagat 180 ggcatcacct ggaccctgga tcaaagctcc gaagtgctcg gcagcggcaa gacactcacc 240 atccaggtga aagagttcgg agacgccggc cagtacacct gccacaaagg cggcgaggtg 300 ctgtcccatt ccctgctgct gctgcacaag aaagaggatg gcatctggtc caccgacatc 360 ctgaaggacc agaaggaacc caagaacaag acctttctga gatgtgaggc caagaactac 420 agcggcaggt tcacctgctg gtggctgaca acaatctcca ccgacctgac cttcagcgtc 480 aagagcagca ggggcagcag cgaccctcaa ggcgtgacat gtggagccgc taccctgagc 540 gctgagagag tcaggggcga caataaggag tacgagtact ccgtggaatg ccaggaggac 600 tccgcctgcc ctgccgccga agagtccctc cctatcgaag tgatggttga tgccgtgcac 660 aagctcaagt atgagaatta caccagcagc tttttcatca gggacatcat caagcccgac 720 ccccccaaaa acctccagct gaaacccctc aagaatagca ggcaggtgga ggtctcctgg 780 gagtatcctg acacctggag caccccccac agctacttct ccctgacctt ctgtgtgcag 840 gtgcagggca agagcaaaag ggagaagaag gatagggtct ttaccgacaa gaccagcgcc 900 acagtgatct gcaggaagaa cgccagcatt tccgtcaggg cccaggacag gtactacagc 960 agcagctggt ccgagtgggc tagcgtgcct tgttccggcg gcggaggatc tggcggaggc 1020 ggaagtggcg gagggggctc tagaaacctc cccgtggcca cacccgaccc tggcatgttc 1080 ccctgcctcc accacagcca gaacctgctg agagccgtga gcaatatgct gcagaaggcc 1140 aggcaaaccc tggagttcta cccctgtacc tccgaggaga ttgaccatga ggacatcaca 1200 aaggacaaaa ccagcaccgt ggaggcctgt ctccccctcg aactgaccaa gaacgagtcc 1260 tgcctgaact ccagggagac atccttcatc accaacggct cctgcctggc ctccagaaag 1320 accagcttca tgatggccct ctgcctgagc agcatctacg aggacctcaa gatgtaccag 1380 gtggagttta aaacaatgaa cgccaagctc ctcatggacc ctaagaggca gattttcctc 1440 gaccagaata tgctggctgt cattgacgag ctgatgcagg ccctcaattt caactccgag 1500 accgtccccc agaagtcctc cctggaagag cccgactttt acaagaccaa gatcaagctc 1560 tgcatcctgc tgcacgcctt cagaattaga gccgtgacca ttgacagggt gatgagctac 1620 ctcaacgcct cctgatgact cgag 1644

<210> SEQ ID NO 97 <211> LENGTH: 2101 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 97 gtcgacgcca ccacatccgc ggcaacgcct ccttggtgtc gtccgcttcc aataacccag 60 cttgcgtcct gcacacttgt ggcttccgtg cacacattaa caactcatgg ttctagctcc 120 cagtcgccaa gcgttgccaa ggcgttgaga gatcatctgg gaagtctttt acccagaatt 180 gctttgattc aggccagctg gtttttcctg cggtgattcg gaaattcgcg aattcctctg 240 gtcctcatcc aggtgcgcgg gaagcaggtg cccaggagag aggggataat gaagattcca 300 tgctgatgat cccaaagatt gaacctgcag accaagcgca aagtagaaac tgaaagtaca 360 ctgctggcgg atcctacgga agttatggaa aaggcaaagc gcagagccac gccgtagtgt 420 gtgccgcccc ccttgggatg gatgaaactg cagtcgcggc gtgggtaaga ggaaccagct 480 gcagagatca ccctgcccaa cacagactcg gcaactccgc ggaagaccag ggtcctggga 540 gtgactatgg gcggtgagag cttgctcctg ctccagttgc ggtcatcatg actacgcccg 600 cctcccgcag accatgttcc atgtttcttt taggtatatc tttggacttc ctcccctgat 660 ccttgttctg ttgccagtag catcatctga ttgtgatatt gaaggtaaag atggcaaaca 720 atatgagagt gttctaatgg tcagcatcga tcaattattg gacagcatga aagaaattgg 780 tagcaattgc ctgaataatg aatttaactt ttttaaaaga catatctgtg atgctaataa 840 ggaaggtatg tttttattcc gtgctgctcg caagttgagg caatttctta aaatgaatag 900 cactggtgat tttgatctcc acttattaaa agtttcagaa ggcacaacaa tactgttgaa 960 ctgcactggc caggttaaag gaagaaaacc agctgccctg ggtgaagccc aaccaacaaa 1020 gagtttggaa gaaaataaat ctttaaagga acagaaaaaa ctgaatgact tgtgtttcct 1080 aaagagacta ttacaagaga taaaaacttg ttggaataaa attttgatgg gcactaaaga 1140 acactgaaaa atatggagtg gcaatataga aacacgaact ttagctgcat cctccaagaa 1200 tctatctgct tatgcagttt ttcagagtgg aatgcttcct agaagttact gaatgcacca 1260 tggtcaaaac ggattagggc atttgagaaa tgcatattgt attactagaa gatgaataca 1320 aacaatggaa actgaatgct ccagtcaaca aactatttct tatatatgtg aacatttatc 1380 aatcagtata attctgtact gatttttgta agacaatcca tgtaaggtat cagttgcaat 1440 aatacttctc aaacctgttt aaatatttca agacattaaa tctatgaagt atataatggt 1500 ttcaaagatt caaaattgac attgctttac tgtcaaaata attttatggc tcactatgaa 1560 tctattatac tgtattaaga gtgaaaattg tcttcttctg tgctggagat gttttagagt 1620 taacaatgat atatggataa tgccggtgag aataagagag tcataaacct taagtaagca 1680 acagcataac aaggtccaag atacctaaaa gagatttcaa gagatttaat taatcatgaa 1740 tgtgtaacac agtgccttca ataaatggta tagcaaatgt tttgacatga aaaaaggaca 1800 atttcaaaaa aataaaataa aataaaaata aattcaccta gtctaaggat gctaaacctt 1860 agtactgagt tacattgtca tttatataga ttataacttg tctaaataag tttgcaattt 1920 gggagatata tttttaagat aataatatat gtttaccttt taattaatga aatatctgta 1980 tttaattttg acactatatc tgtatataaa atattttcat acagcattac aaattgctta 2040 ctttggaata catttctcct ttgataaaat aaatgagcta tgtattaaaa aaaaaaaaaa 2100 a 2101 <210> SEQ ID NO 98 <211> LENGTH: 925 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 98 gtcgacgcca ccccagagag gggcaggctg gtcccctgac aggttgaagc aagtagacgc 60 ccaggagccc cgggaggggg ctgcagtttc cttccttcct tctcggcagc gctccgcgcc 120 cccatcgccc ctcctgcgct agcggaggtg atcgccgcgg cgatgccgga ggagggttcg 180 ggctgctcgg tgcggcgcag gccctatggg tgcgtcctgc gggctgcttt ggtcccattg 240 gtcgcgggct tggtgatctg cctcgtggtg tgcatccagc gcttcgcaca ggctcagcag 300 cagctgccgc tcgagtcact tgggtgggac gtagctgagc tgcagctgaa tcacacagga 360 cctcagcagg accccaggct atactggcag gggggcccag cactgggccg ctccttcctg 420 catggaccag agctggacaa ggggcagcta cgtatccatc gtgatggcat ctacatggta 480 cacatccagg tgacgctggc catctgctcc tccacgacgg cctccaggca ccaccccacc 540 accctggccg tgggaatctg ctctcccgcc tcccgtagca tcagcctgct gcgtctcagc 600 ttccaccaag gttgtaccat tgcctcccag cgcctgacgc ccctggcccg aggggacaca 660 ctctgcacca acctcactgg gacacttttg ccttcccgaa acactgatga gaccttcttt 720 ggagtgcagt gggtgcgccc ctgaccactg ctgctgatta gggtttttta aattttattt 780 tattttattt aagttcaaga gaaaaagtgt acacacaggg gccacccggg gttggggtgg 840 gagtgtggtg gggggtagtg gtggcaggac aagagaaggc attgagcttt ttctttcatt 900 ttcctattaa aaaatacaaa aatca 925 <210> SEQ ID NO 99 <211> LENGTH: 141 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 99 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcgcaag 60 tctatgttgt agtaaatttg ggcgtaaccg agtaagattt ggccattttc gcgggaaaac 120 tgaataagag gaagtgaaat c 141 <210> SEQ ID NO 100 <211> LENGTH: 142 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 100 acaggaagtg acatgttgca agtgtggcgg aacacatgta agcgacggat gtggcgcaag 60 tctatgttgt agtaaatttg ggcgtaaccg agtaagattt ggccattttc gcgggaaaac 120 tgaataagag gaagtgaaat ct 142 <210> SEQ ID NO 101 <211> LENGTH: 129 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 101 acaggaagtg acaattttcg cgcggtttta ggcggatgtg gcgcaagtct atgttgtagt 60 aaatttgggc gtaaccgagt aagatttggc cattttcgcg ggaaaactga ataagaggaa 120 gtgaaatct 129 <210> SEQ ID NO 102 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 102 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacggc ggaagtgtga attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataagagg aagtgaaatc t 201 <210> SEQ ID NO 103 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 103 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacggc ggaagtgtga attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataagagg atgtgaaatc t 201 <210> SEQ ID NO 104 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 104 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacggc ggaagtgtga attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180 gaataggcgg aagtgtgatc t 201 <210> SEQ ID NO 105 <211> LENGTH: 201 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 105 ggcggaagtg tgatgttgca agtgtggcgg aacacatgta agcgacggat gtggcaaaag 60 tgacgttttt ggtgtgcgcc ggtgtacaca ggaagtgaca attttcgcgc ggttttagac 120 ggatgtggca gtaaatttgg gcgtaaccga gtaagatttg gccattttcg cgggaaaact 180

gaataggcgg aagtgtgatc t 201 <210> SEQ ID NO 106 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106 Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile 1 5 10 15 Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys 20 25 30 Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu 35 40 45 Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe 50 55 60 Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe 65 70 75 80 Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser 85 90 95 Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr 100 105 110 Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala 115 120 125 Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu 130 135 140 Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu 145 150 155 160 Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu 165 170 175 His <210> SEQ ID NO 107 <211> LENGTH: 193 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 107 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Arg Met Lys Gln Ile Glu Asp Lys Ile Glu 20 25 30 Glu Ile Leu Ser Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile 35 40 45 Lys Lys Leu Ile Gly Glu Arg Gly Gly Gly Ser Gly Gly Gly Ser Gly 50 55 60 Gly Gly Ser Glu Thr Ala Lys Glu Pro Cys Met Ala Lys Phe Gly Pro 65 70 75 80 Leu Pro Ser Lys Trp Gln Met Ala Ser Ser Glu Pro Pro Cys Val Asn 85 90 95 Lys Val Ser Asp Trp Lys Leu Glu Ile Leu Gln Asn Gly Leu Tyr Leu 100 105 110 Ile Tyr Gly Gln Val Ala Pro Asn Ala Asn Tyr Asn Asp Val Ala Pro 115 120 125 Phe Glu Val Arg Leu Tyr Lys Asn Lys Asp Met Ile Gln Thr Leu Thr 130 135 140 Asn Lys Ser Lys Ile Gln Asn Val Gly Gly Thr Tyr Glu Leu His Val 145 150 155 160 Gly Asp Thr Ile Asp Leu Ile Phe Asn Ser Glu His Gln Val Leu Lys 165 170 175 Asn Asn Thr Tyr Trp Gly Ile Ile Leu Leu Ala Asn Pro Gln Phe Ile 180 185 190 Ser

Claims

1. A pharmaceutical composition comprising an effective amount of a recombinant adenoviral vector comprising: a transgene insertion site located between the start site of adenoviral E1b-19K and the start site of adenoviral E1b-55K, wherein a first DNA sequence and a second DNA sequence are each inserted into the transgene insertion site; wherein the first DNA sequence encodes a polypeptide selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand, and wherein the second DNA sequence encodes a polypeptide selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand; wherein the adenoviral vector comprises a modified adenoviral E1a regulatory sequence wherein at least one Pea3 binding site, or a functional portion thereof, of the recombinant adenoviral vector is modified or deleted.

2. The pharmaceutical composition of claim 1, wherein the adenoviral vector comprises an IRES element or encodes a self-cleaving 2A peptide sequence between the first DNA sequence and the second DNA sequence.

3. The pharmaceutical composition of claim 1, comprising a modified E3 region.

4. The pharmaceutical composition of claim 1, comprising an intact E3 region.

5. The pharmaceutical composition of claim 3, further comprising a third DNA sequence inserted into the E3 region, wherein the third DNA sequence encodes a polypeptide selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, or a human OX40 ligand.

6. The pharmaceutical composition of claim 1, wherein the adenoviral vector comprises a nucleic acid sequence at least 95% identical in an E3 region to vector d1327.

7. The pharmaceutical composition of claim 1, wherein the chimeric human IL-12 polypeptide comprises a p40 polypeptide, a p35 polypeptide, and a linker polypeptide.

8. The pharmaceutical composition of claim 1, wherein the chimeric human IL-12 polypeptide comprises a sequence as set forth in SEQ ID NO:46.

9. The pharmaceutical composition of claim 1, formulated for systemic administration.

10. The pharmaceutical composition of claim 1, formulated for intratumoral administration.

11. A pharmaceutical composition comprising an effective amount of a recombinant adenoviral vector comprising: a. a first transgene insertion site located between the start site of adenoviral E1b-19K and the start site of adenoviral E1b-55K; b. a second transgene insertion site located in adenoviral E3 region; c. a first DNA sequence, present in the first transgene insertion site, encoding one or a plurality of polypeptides selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand; and d. a second DNA sequence, present in the second transgene insertion site, encoding one or a plurality of polypeptides selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand, wherein the adenoviral vector comprises a modified adenoviral E1a regulatory sequence.

12. The pharmaceutical composition of claim 11, further comprising a third DNA sequence inserted into a third transgene insertion site, encoding one or a plurality of polypeptides selected from the group consisting of: a chimeric human IL-12, a human IL-7, an anti-CTLA-4 antibody, an IL-10Rtrap, a human CD70, a human IL-2 polypeptide, a human CD40 ligand, and a human OX40 ligand.

13. The pharmaceutical composition of claim 8, wherein at least one of the first DNA sequence, the second DNA sequence, and the third DNA sequence independently comprises an IRES element and/or a self-cleaving 2A peptide.

14. The pharmaceutical composition of claim 11, wherein at least one E1a regulatory sequence Pea3 binding site, or a functional portion thereof of the adenoviral vector, is modified or deleted.

15. The pharmaceutical composition of claim 11, wherein a sequence between two Pea3 sites of the adenoviral vector is deleted.

16. The pharmaceutical composition of claim 11, comprising a modified E3 region.

17. The pharmaceutical composition of claim 11, wherein the adenoviral vector comprises a nucleic acid sequence at least 95% identical in an E3 region to vector d1327.

18. The pharmaceutical composition of claim 11, wherein the chimeric human IL-12 polypeptide comprises a p40 polypeptide, a p35 polypeptide, and a linker polypeptide.

19. A method for treating a tumor in a human subject in need thereof, comprising administering to the human with the tumor a therapeutic amount of the pharmaceutical composition of claim 1 by systemic or intratumoral administration.

20. A method for treating a tumor in a human subject in need thereof, comprising administering to the human with the tumor a therapeutic amount of the pharmaceutical composition of claim 11 by systemic or intratumoral administration.