ONCOLYTIC ADENOVIRUS ENCODING A B7 PROTEIN

Abstract

The present disclosure provides a replication competent oncolytic adenovirus with selectivity for cancer cells, wherein the adenovirus comprises a transgene under the control of a promoter endogenous to the virus, wherein the transgene comprises a DNA sequence encoding a B7 protein or an active fragment thereof, compositions comprising same, methods of generating the viruses, and use of the viruses and compositions in treatment, particularly in the treatment of cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of U.S. patent application Ser. No. 15/570,100, filed Oct. 27, 2017, now allowed, which is a 35 U.S.C. .sctn. 371 national phase application from International Application No. PCT/EP2016/059609, filed Apr. 29, 2016, and published under PCT Article 21(2) in English, which designated the U.S., and claims the benefit of priority to United Kingdom Patent Application Nos. GB 1507419.8 filed Apr. 30, 2015; GB 1516936.0 filed Sep. 24, 2015; and GB 1522013.0 filed Dec. 14, 2015, each of which is hereby incorporated by reference in its entirety including all tables, figures and claims.

[0002] The present disclosure relates to an oncolytic adenovirus comprising a transgene encoding at least a B7 protein such as CD80 or an active fragment thereof, compositions comprising the same and use of the virus and compositions in treatment, particularly in the treatment of cancer.

SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 5, 2021, is named 314641-00047_Sequence_Listing.TXT and is 526 kilobytes in size.

BACKGROUND

[0004] Cancer is still a huge social burden to society in terms of the hardship and suffering of patients and their loved ones, and also in terms of the high financial cost of treating, caring for and supporting patients. It is now thought that the immune system of healthy individuals clears cancerous cells routinely. However, in those patients with cancer one or more of the defense mechanisms involved in this clearance is/are down regulated or turned off completely.

[0005] It is now known that tumors change their microenvironment to make it more permissive to their growth. This occurs by the tumor releasing extracellular signals that, for example, promote tumor angiogenesis and/or induce local immune suppression or immune tolerance.

[0006] It is clear from many different preclinical and clinical studies that the microenvironment within tumours can suppress the development and activity of anti-tumour immune responses, with a wide variety of mechanisms being shown to potentially play a role. In particular immuno-suppressive mechanisms ultimately prevent T-cell responses from mediating the killing of tumour cells. Suppressive mechanisms may include the exclusion of T-cells from entering tumour tissues, inhibiting activation of T-cells that do enter the tumour and the modulation of tumour cell proteins which reduces the ability of T-cells to recognize or respond to them. The importance of such immunosuppressive pathways in supporting tumour progression has been particularly highlighted by the clinical efficacy shown by antibodies to receptors in two such suppressive pathways, CTLA4 and PD-1/PDL1, which has led to their marketing approval for the treatment of melanoma and other cancers.

[0007] B7 is a type of peripheral membrane protein found on activated antigen presenting cells (APC) that, when paired with either a CD28 or CD152 (CTLA-4) surface protein on a T cell, can produce a co-stimulatory signal or a co-inhibitory signal to enhance or decrease the activity of a MHC-TCR signal between the antigen presenting cell (APC) and the T cell, respectively. Besides being present on activated APCs, B7 can also be found on T-cells themselves.

[0008] There are several steps to activation of the immune system against an antigen. The T cell receptor must first interact with a complex of its specific peptide antigen (Ag) bound to a major histocompatibility complex (MHC) surface protein. The CD4 or CD8 proteins on the T-cell surface interact with the MHC to help stabilize the MHC/Ag interaction with the T-cell receptor complex, which comprises both the antigen-binding chain dimers (alpha/beta or gamma/delta) and the CD3 signaling complex (comprising gamma, delta, epsilon and zeta chains). This is also referred to as "Signal 1" and its main purpose is to provide the initial signaling and guarantee antigen specificity of the T cell activation.

[0009] However, MHC binding is insufficient by itself for stimulating full effector T cell differentiation and activation. In fact, lack of further stimulatory signals can render the T cell anergic. The co-stimulatory signals necessary to continue the immune response can come from B7-CD28 and CD40-CD40L interactions. There are other activation signals which play a role in immune responses. For example, in the TNF family of molecules, the protein 4-1BB (CD137) on the T cell may bind to 4-1BBL on the APC.

[0010] The B7 (CD80/B7-1 and/or CD86/B7-2) protein is present on the APC surface, and it interacts with the CD28 receptor on the T cell surface. This is one source of "Signal 2" (cytokines can also contribute to T-cell activation, which may be referred to as "Signal 3"). This interaction produces a series of downstream signals which promote the target T cell's survival, activation and differentiation into an effector cell that can mediate aspects of the immune response, such as killing of virus infected cells or tumour cells, and the recruitment of inflammatory cells.

[0011] Usually for initiating a T-cell response, the stimulatory signal and the co-stimulatory signal are provided by an antigen presenting cell in order to induce both CD4 and CD8 T-cell responses. But effector CD8 T-cells recognize their Ag associated with MHC class I molecules which are present on most nucleated cells, including tumour cells. However, the present inventors have reason to believe that the signals to activate T cells do not need to come from the same cell or cell type. Therefore it would be useful to provide one or more of these signals (i.e. the stimulatory signal and/or the co-stimulatory signal) to the immune system, for example on the surface of a cancer cell.

[0012] Currently there is much interest in inhibiting PD-1 (programmed cell death protein 1) and/or its ligand PDL1 (also known as B7-H1) activity because this pathway is thought to play an important role in down-regulating immune responses, for example in cancers.

[0013] However, some work done suggests that CD80 (B7-1) not only acts as a T-cell co-stimulator by binding to CD28 on the T-cell, it can also bind to PDL1, for example when expressed in the same cell membrane, and block PDL1-PD1 inhibitory signaling interactions. Thus, by acting in two different ways, CD80 may be a viable and potentially more useful molecule for restoring or enhancing the activation of human T cells. Soluble forms of CD80 also seem to be capable of counteracting PDL1-PD1 mediated T cell inhibition, see for example Haile et al Soluble CD80 Restores T Cell Activation and Overcomes Tumor Cell Programmed Death Ligand 1-Mediated Immune Suppression J Immunol 2013; 191:2829-2836. A CD80-Fc fusion protein has been generated and is being tested for safety and efficacy, see the Journal of Immunology, 2014, 193: 3835-3841.

[0014] The present inventors believe that the B7 proteins or an active fragment thereof delivered and expressed by an oncolytic virus, for example on the surface of a cancer cell, would be useful in activating the patient's own immune system to fight the cancer.

[0015] Furthermore, B7 proteins, such as CD80, if simply administered systemically have the potential to stimulate immune responses systemically in an undesirable way. The present inventors believe that a more sophisticated delivery of these proteins is required to create a suitable therapeutic window where beneficial therapeutic effects are realized and off target effects are minimized.

SUMMARY OF THE DISCLOSURE

[0016] Thus there is provided an oncolytic adenovirus with selectivity for cancer cells, wherein the adenovirus comprises a transgene under the control of a promoter endogenous to the virus, wherein the transgene comprises a DNA sequence encoding a B7 protein or an active fragment thereof. This is beneficial because the oncolytic viruses according to the present disclosure preferentially infect cancer cells and thus penetrate the microenvironment created by the cancer. Once in the cancer cells the B7 proteins encoded by the virus can be expressed, for example on the cell surface (i.e. cancer cell surface). This is advantageous because the B7 protein is then in the desired location where it can be biologically active.

[0017] In one embodiment the B7 protein encoded comprises a sequence capable of anchoring the protein on the surface of a cell, for example a transmembrane domain sequence, GPI anchor or the like.

[0018] Thus in one embodiment the cancer cell is infected with a virus of the present disclosure which expresses a B7 protein or molecule, in particular on the surface of the cancer cell, wherein the B7 protein is suitable for providing at least the co-stimulatory signal i.e. signal 2 to activate a T cell, and/or may bind to and inhibit the activity of PD-L1 expressed on the surface of the cancer cell or other cells in the local microenvironment.

[0019] In one embodiment the B7 sequence comprises a transmembrane element from a B7 protein, for example a transmembrane element native to the particular B7 protein or a transmembrane domain from a "different" B7 protein to that being particularly expressed.

[0020] B7 proteins are surface expressed proteins and can also be employed to carry additional proteins to the cancer cell surface, for example where at least the transmembrane domain of a B7 protein is attached to an additional protein.

[0021] Thus in one aspect there is provided a replication competent oncolytic adenovirus with selectivity for cancer cells, wherein the adenovirus comprises a transgene under the control of a promoter endogenous to the virus, wherein the transgene comprises a DNA sequence encoding a B7 protein or an active fragment thereof.

[0022] Also provided is a replication competent oncolytic virus according to claim 1, wherein the B7 protein or active fragment thereof is independently selected from the group comprising B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5 and B7-H6, in particular wherein the B7 protein is B7-1 (CD80) or an active fragment thereof.

[0023] In one embodiment the replication competent oncolytic virus is a group B adenovirus.

[0024] In one embodiment the replication competent oncolytic virus is a chimeric virus.

[0025] In one embodiment the replication competent oncolytic virus has a backbone is enadenotucirev (also referred to as EnAd).

[0026] In one embodiment the replication competent oncolytic virus has a formula (I):

5'ITR-B1-BA-B2-BX-BB-BY-B3-3'ITR (I)

[0027] B.sub.1 comprises: E1A, E1B or E1A-E1B;

[0028] B.sub.A is E2B-L1-L2-L3-E2A-L4;

[0029] B.sub.2 is a bond or comprises E3 or a transgene, for example under an endogenous or exogenous promoter;

[0030] B.sub.X is a bond or a DNA sequence comprising: a restriction site, one or more transgenes or both;

[0031] B.sub.B comprises L5;

[0032] B.sub.Y comprises a transgene encoding a B7 protein or an active fragment thereof; and

[0033] B.sub.3 is a bond or comprises E4.

[0034] In one embodiment the replication competent oncolytic virus according to any one of claims 1 to 7, wherein the B7 protein or active fragment thereof comprises a transmembrane sequence, for example a transmembrane domain from a PDGF receptor, or GPI anchor suitable for anchoring the protein or fragment in a cell membrane.

[0035] In one embodiment the replication competent oncolytic virus further comprises a second transgene, for example encoding a polypeptide selected from the group comprising a cytokine, a chemokine, an antagonistic antibody molecule or fragment thereof, and an agonistic antibody molecule or fragment thereof.

[0036] In one embodiment the second and third transgene, for example encoding two different polypeptides selected from the group comprising a cytokine, a chemokine, an antibody, such as an antagonistic antibody molecule or fragment thereof, or an agonistic antibody molecule or fragment thereof.

[0037] In one embodiment the second or third transgene encodes a cytokine, selected from the group comprising IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15, and IL-12.

[0038] In one embodiment the second or third transgene encodes a chemokine, selected from the group comprising MIP1.alpha., IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21.

[0039] In one embodiment a cytokine and a chemokine combination is encoded by the virus selected from the group comprising Mip1a and Flt3 ligand, and MIP1.alpha. and IFN.alpha..

[0040] In one embodiment the virus encodes an antibody molecule or fragment thereof for example comprising a transmembrane sequence or GPI anchor such that it is a cell membrane-anchored form or a transmembrane domain, for example from a PDGF receptor. In one embodiment the antibody molecule or binding fragment thereof comprises an anti-human CD3 antigen binding domain.

[0041] In one embodiment the antibody molecule is an inhibitor, for example selected from the group comprising an inhibitor of an angiogenesis factor, such as an anti-VEGF antibody molecule, and inhibitor of T cell deactivation factors, such an anti-CTLA-4 antibody molecule.

[0042] In one embodiment the antibody molecule is an agonist, for example of one or more selected from the group comprising CD40, GITR, OX40, CD27 and 4-1BB.

[0043] In one embodiment an exogenous protein or proteins encoded by the virus is/are a form suitable for expression on a cancer cell surface.

SUMMARY OF THE FIGURES

[0044] FIG. 1A shows some of the key molecules involved in T-cell recognition of antigen presenting cells or tumor cells, and some of the signaling events induced in the responding T-cell.

[0045] FIG. 1B shows some of the key molecules involved in T-cell recognition of antigen presenting cells or tumor cells, and some of the signaling events induced in the responding T-cell.

[0046] FIG. 2 shows some of the B7 family ligands and binding partners from the CD28 family of receptors.

[0047] FIG. 3A shows a schematic of a transgene cassette for a virus expressing human CD80.

[0048] FIG. 3B shows a schematic of a transgene cassette for a virus co-expressing human IFN.alpha. and human CD80.

[0049] FIG. 3C shows a schematic of a transgene cassette for a virus co-expressing OKT3 scFv and human CD80.

[0050] FIG. 3D shows a schematic for a virus co-expressing human Flt3L, human MIP1.alpha. and human IFN.alpha..

[0051] FIG. 3E shows a schematic for a virus co-expressing human Flt3L, human MIP1.alpha. and human CD80.

[0052] FIG. 3F shows a schematic for a virus co-expressing human IFN.alpha., human MIP1.alpha. and human CD80.

[0053] FIG. 3G shows a schematic of the open reading frame (ORF) of the OKT3 scFv.

[0054] FIG. 4A shows replication of EnAd (ColoAd1) and human CD80 encoding virus NG-330 in HT-29 tumour cells.

[0055] FIG. 4B shows replication of EnAd (ColoAd1) and human CD80 encoding virus NG-330 in A549 tumour cells.

[0056] FIG. 5A shows expression of CD80 in the membrane of A549 tumour cells by fluorescent immunostaining at different times after infection with NG-330.

[0057] No expression of CD80 on the cell membrane was observed with EnAd or uninfected tumour cells (UIC).

[0058] FIG. 5B shows expression of CD80 in the membrane of HT-29 tumour cells by fluorescent immunostaining at different times after infection with NG-330.

[0059] No expression of CD80 on the cell membrane was observed with EnAd or uninfected tumour cells (UIC).

[0060] FIG. 6 shows comparable oncolytic potencies of EnAd and NG-330 in a HT-29 cytoxicity assay. Thus NG-330 retains its oncolytic properties whilst also carrying a transgene.

[0061] FIG. 7A shows comparable oncolytic potency of EnAd and the CD80+IFN.alpha. expressing NG-343 virus over a period of up to 72 hours.

[0062] FIG. 7B shows secretion of IFN.alpha. by NG-343 infected HT-29 and A549 tumour cells over a period of up to 72 hours.

[0063] FIG. 8A shows expression of CD80 and tumour cell killing at 48 or 72 hours post infection by FACS analysis using anti-CD80 immunostaining together with a cell viability stain in uninfected control (UIC) A549 tumour cells.

[0064] FIG. 8B shows expression of CD80 and tumour cell killing at 48 or 72 hours post infection by FACS analysis using anti-CD80 immunostaining together with a cell viability stain in A549 tumour cells infected with EnAd.

[0065] FIG. 8C shows expression of CD80 and tumour cell killing at 48 or 72 hours post infection by FACS analysis using anti-CD80 immunostaining together with a cell viability stain in A549 tumour cells infected with NG-343 Isotype.

[0066] FIG. 8D shows expression of CD80 and tumour cell killing at 48 or 72 hours post infection by FACS analysis using anti-CD80 immunostaining together with a cell viability stain in A549 tumour cells infected with NG-343. CD80 could be detected at the cell surface of both live and dead NG-343 treated cells but not EnAd or uninfected control (UIC) A549 tumour cells (FIGS. 8A-D).

[0067] FIG. 8E shows similar CD80 expression was seen with both A549 and HT-29 tumour cells.

[0068] FIG. 9A shows virus replication with both EnAd and NG-343 in tumour (HT-29) and non-tumour (MRC5, WI38 and bronchial epthelial cells) cells.

[0069] FIG. 9B shows IFN.alpha. secretion following infection.

[0070] FIG. 9C shows CD80 expression following infection.

[0071] Thus, FIGS. 9A to 9C show that there is comparable virus replication with both EnAd and NG-343 in tumour and non-tumour cells, with the latter showing much lower levels of replication, IFN.alpha. secretion and CD80 expression following NG-343 infection only detected in HT-29 tumour cells.

[0072] FIG. 10 shows that A549 tumour cells infected with NG-343 can induce increased surface levels of both CD80 and PD-L1 on the surface of DCs in PBMC co-cultures when compared to EnAd infected or uninfected tumour cell culture.

[0073] FIG. 11A shows expression of IFN.alpha. by HT-29 tumour cells infected with NG-347 virus.

[0074] FIG. 11B shows expression of IFN.alpha. by A549 tumour cells infected with NG-347 virus.

[0075] FIG. 11C shows CD80 expression by HT-29 and A549 tumour cells infected with NG-347, EnAd or NG-347 Isotype Control.

[0076] FIG. 12A shows expression of MIP1.alpha. byA549 tumour cells infected with NG-345 virus.

[0077] FIG. 12B shows IFN.alpha. expression by A549 tumour cells infected with NG-345 virus.

[0078] FIG. 12C shows expression of Flt3L by A549 tumour cells infected with NG-345 virus.

[0079] FIG. 13A shows oncolytic potency of EnAd and NG-347 viruses in an HT-29 cytotoxicity assay.

[0080] FIG. 13B shows oncolytic potency of EnAd and NG-348 viruses in an HT-29 cytotoxicity assay. NG-347 and NG-348 oncolytic potency was comparable to EnAd.

[0081] FIG. 13C shows infectivity of EnAd, NG-347 and NG-348 viruses in an HT-29 cytotoxicity assay.

[0082] Thus, FIGS. 13A to 13C show comparable oncolytic potency and infectivity of EnAd, NG-347 and NG-348 viruses.

[0083] FIG. 14A shows CD80 expression at 24 hours on the cell surface of A549 tumour cells infected with either NG-347 or NG-348 viruses.

[0084] FIG. 14B shows CD80 expression at 48 hours on the cell surface of A549 tumour cells infected with either NG-347 or NG-348 viruses.

[0085] FIG. 14C shows CD80 expression at 72 hours on the cell surface of A549 tumour cells infected with either NG-347 or NG-348 viruses.

[0086] FIG. 14D shows normalised cell counts and CD80 expression of A549 tumour cells at 24, 48 and 72 hours.

[0087] Thus, FIGS. 14A to 14D show high CD80 expression by 48 hours on the cell surface of A549 tumour cells infected with either NG-347 or NG-348 viruses but little or no CD80 expression following EnAd infection.

[0088] FIG. 15A shows CD80 expression at 48 hours on the cell surface of DLD-1 tumour cells infected with either NG-347 or NG-348 viruses.

[0089] FIG. 15B shows CD80 expression at 72 hours on the cell surface of DLD-1 tumour cells infected with either NG-347 or NG-348 viruses.

[0090] FIG. 15C shows CD80 expression at 96 hours on the cell surface of DLD-1 tumour cells infected with either NG-347 or NG-348 viruses.

[0091] FIG. 15D shows normalised cell counts and CD80 expression of DLD-1 tumour cells at 24, 48 and 72 hours.

[0092] Thus, FIGS. 15A to 15D show high CD80 expression by 48 hours on the cell surface of DLD-1 tumour cells infected with either NG-347 or NG-348 viruses but little or no CD80 expression following EnAd infection.

[0093] FIG. 16 shows CD80 expression on EpCam.sup.+ A549 cells infected with NG-348 and co-cultured with human CD3.sup.+ T-cells, but not when infection was with EnAd.

[0094] FIG. 17A shows CD25 is upregulated on human CD3.sup.+ T-cells following co-culture with NG-348 infected A549 cells, but not when infection was with EnAd.

[0095] FIG. 17B shows the percentage of CD25.sup.+ cells was increased.

[0096] FIG. 17C shows the level of CD25 expression per cell was increased.

[0097] FIG. 18A shows CD25 is upregulated on human CD3.sup.+ CD4.sup.+ T-cells following co-culture with NG-348 infected A549 cells in comparison to T-cells co-cultured with uninfected A549 cells or A549 cells infected with EnAd.

[0098] FIG. 18B shows CD25 is upregulated on human CD3+CD4.sup.-_T-cells following co-culture with NG-348 infected A549 cells in comparison to T-cells co-cultured with uninfected A549 cells or A549 cells infected with EnAd.

[0099] FIG. 18C shows the percentage of CD3.sup.+ CD4.sup.+ T-cells expressing CD25 co-cultured with uninfected A549 cells or A549 cells infected with EnAd or NG-348.

[0100] FIG. 18D shows the percentage of CD3.sup.+ CD4-T-cells expressing CD25 co-cultured with uninfected A549 cells or A549 cells infected with EnAd or NG-348.

[0101] Thus, FIGS. 18A-D show CD25 is upregulated on both CD4.sup.+ and CD4-(primarily CD8) human CD3.sup.+ T cell subsets following co-culture with NG-348 infected A549 cells, but not when infection was with EnAd.

[0102] FIG. 19A shows the percentage of CD3.sup.+ cells expressing HLA-DR after co-culture with uninfected A549 cells (UIC) or A549 cells infected with EnAd or NG348.

[0103] FIG. 19B shows the HLA-DR expression of CD3.sup.+ cells after co-culture with A549 cells infected with EnAd or NG-348 compared to controls.

[0104] Thus, FIGS. 19A-B show low level of HLA-DR expression on human CD3.sup.+ T cells following co-culture with NG-348 or EnAd infected A549 cells.

[0105] FIG. 20A shows upregulation of CD107a expression on the surface of live, CD3.sup.+ T cells following co-culture with NG-348 infected A549 cells, but not when co-cultured with A549 cells infected with EnAd or uninfected A549 cells.

[0106] FIG. 20B shows the percentage of CD3 cells expressing CD107a.sup.+ after co-culture with uninfected A549 cells or A549 cells infected with EnAd or NG-348.

[0107] FIG. 21A shows CD107a is upregulated on human CD3.sup.+ CD4.sup.+ T-cells following co-culture with NG-348 infected A549 cells but is not upregulated when co-cultured with A549 cells infected with EnAd.

[0108] FIG. 21B shows CD107a is upregulated on human CD3+ CD4.sup.-_T-cells following co-culture with NG-348 infected A549 cells but is not upregulated when co-cultured with A549 cells infected with EnAd.

[0109] FIG. 21C shows the percentage of CD107a expressing CD3.sup.+ CD4.sup.+ T-cells following co-culture with uninfected A549 cells (UIC), A549 infected with EnAd or NG-348.

[0110] FIG. 21D shows the percentage of CD107a expressing CD3.sup.+ CD4.sup.-T-cells following co-culture with uninfected A549 cells (UIC), or A549 cells infected with EnAd or NG-348.

[0111] Thus, FIGS. 21A-D show induction of CD107a expression on the surface of both CD4.sup.+ and CD4.sup.- CD3.sup.+ T cell subsets following co-culture with NG-348 infected A549 cells, but not when infection was with EnAd.

[0112] FIG. 22A shows induction of IL-2 production by CD3.sup.+ T cells following co-culture with NG-348 infected A549 cells, but no IL-2 when infection was with EnAd.

[0113] FIG. 22B shows induction of IFN.gamma. production by CD 3.sup.+ T cells following co-culture with NG-348 infected A549 cells, but only low levels of IFN.gamma. when infection was with EnAd.

[0114] FIG. 23A shows induction of IFN.gamma. production by CD4.sup.+ CD3.sup.+ T cells following co-culture with NG-348 infected A549 cells, but no IFN.gamma. when infection was with EnAd.

[0115] FIG. 23B shows induction of IFN.gamma. production by CD8.sup.+ CD3.sup.+ T cells following co-culture with NG-348 infected A549 cells, but low IFN.gamma. when infection was with EnAd.

[0116] FIG. 24A shows CD69 expression CD3.sup.+ T-cells following co-culture with uninfected A549 cells, and A549 cells infected with EnAd or NG-347.

[0117] FIG. 24B shows the percentage of CD3.sup.+ T-cells expressing CD69 after co-culture with uninfected A549 cells, and A549 cells infected with EnAd or NG-347.

[0118] Thus, FIGS. 24A-B show CD69 is upregulated on more human CD3.sup.+ T-cells following co-culture with NG-347 infected A549 cells than when infection was with EnAd.

[0119] FIG. 25 shows induction of IFN.gamma. production by human CD3.sup.+ T cells following co-culture with NG-347 infected A549 cells, but not when infection was with EnAd.

[0120] FIG. 26A shows a schematic of the NG-348A transgene cassette.

[0121] FIG. 26B shows a schematic of the NG-420 transgene cassette.

[0122] FIG. 26C shows a schematic of the NG-420A transgene cassette.

[0123] FIG. 27 shows genome replication and hexon gene expression (mRNA levels) for EnAd, NG-347, and NG-348 in MRC-5 fibroblast cells compared to A549 tumour cells

[0124] FIG. 28 shows CD80 and anti-CD3-scFv transgene mRNA and CD80 trasngene protein (flow cytometry) expression for virus NG-348 in MRC-5 fibroblast cells compared to A549 tumour cells.

[0125] FIG. 29 shows CD80 transgene mRNA and CD80 transgene protein for virus NG-347 in MRC-5 fibroblast cells compared to A549 tumour cells.

[0126] FIG. 30 shows mRNA and secreted protein levels of MIP1.alpha. and IFN.alpha. generated by virus NG-347 in MRC-5 fibroblast cells compared to A549 tumour cells.

[0127] FIG. 31 shows genome replication and hexon gene expression (mRNA levels) for EnAd, NG-347, and NG-348 in purified human T-cell cultures.

[0128] FIG. 32 shows CD80 and anti-CD3 scFv transgene mRNA and protein expression (flow cytometry) for virus NG-348 in human T-cells compared to A549 tumour cells.

[0129] FIG. 33 shows CD80 transgene mRNA and CD80 transgene protein for virus NG-347 in purified human T-cells compared to A549 tumour cells FIG. 34 shows IFN.alpha. and MIP1.alpha. transgene mRNA generated by virus NG-347 in T cells compared to A549 tumour cells.

[0130] FIG. 35 shows NG-347 and NG-348 genome replication and hexon gene expression by human PBMCs compared to A549 tumour cells.

[0131] FIG. 36 shows CD80 and anti-CD3 scFv mRNA generated by virus NG-348 by PBMCs compared to A549 tumour cells.

[0132] FIG. 37 shows CD80, IFN.alpha. and MIP1.alpha. mRNA generated by virus NG-347 by PBMCs compared to A549 tumour cells.

[0133] FIG. 38A shows the similar activation of human dendritic cells by EnAd, NG-347 and NG-348 virus particles, as measured by down-regulation of CD14 expression.

[0134] FIG. 38B shows the shows the similar activation of human dendritic cells by EnAd, NG-347 and NG-348 virus particles, as measured by upregulation of CD80 on the cell surface.

[0135] FIG. 39A shows similar particle-mediated MIP1.alpha. and IFN.alpha. protein secretion from PBMCs cultured with NG-348 compared to EnAd.

[0136] FIG. 39B shows similar particle-mediated MIP1.alpha. and IFN.alpha. protein secretion from PBMCs cultured with NG-347 compared to EnAd.

[0137] FIG. 40 shows NG-347 or NG-348 genome replication in co-cultures or T-cells or PBMCs with MRC-5 fibroblast cells compared to co-cultures with A549 tumour cells.

[0138] FIG. 41 shows INF.gamma. secreted by PBMCs or T-cells co-cultured with MRC-5 fibroblast cells compared to A549 tumour cells, and treated with EnAd or virus NG-348.

[0139] FIG. 42 shows MIP11a and IFN.alpha. secreted by human dendritic cells treated with EnAd, NG-347 or NG-348 virus particles.

[0140] FIG. 43 shows NF.kappa.B and IFN reporter gene activation in JurkatDual reporter T-cells co-cultured with EnAd, NG-347 or NG-348 infected A549 tumour cells.

[0141] FIG. 44 shows NF-.kappa.B-luciferase reporter activity generated by JurkatDual reporter T-cells co-cultured with EnAd, NG-347, NG-348 or NG-420 treatedA549 HCT-116, DLD and HT29 tumour cells.

[0142] FIG. 45 shows NF-.kappa.B-luciferase reporter activity generated by JurkatDual cells co-cultured with either A549 or HT29 tumour cells infected with virus NG-348 and virus NG-420 as a function of virus particles added.

[0143] FIG. 46 shows the pharmacokinetics of EnAd and virus NG-348 in blood; blood cytokine levels after exposure to EnAd or virus NG-348; tissue biodistribution of EnAd or NG-348 viruses 6 or 24 hours after IV administration to CD1 mice.

[0144] FIG. 47 shows the pharmacokinetics in blood of EnAd, NG-347 and NG-348 viruses following IV administration to CB17-SCID mice bearing a subcutaenous HCT-116 tumour xenograft.

[0145] FIG. 48A shows the tissue distribution of EnAd, NG-347 and NG-348 viruses 6 hours post intravenous dosing in tumour-bearing CB17-SCID mice.

[0146] FIG. 48B shows virus genomes in HCT-116 tumour xenografts at day 7 and day 14-21 following intravenous or intra-tumoral dosing of EnAd, NG-347 or NG-348.

[0147] FIG. 49 shows virus hexon mRNA generated in HCT-116 tumour xenografts by EnAd, NG-347 or NG-348 viruses on day 7 or 14-21 following intravenous or intra-tumoral dosing.

[0148] FIG. 50 shows mRNA levels for hexon and CD80 transgene in HCT-116 tumour xenografts 7 or 21 days following intravenous dosing with virus NG-348.

[0149] FIG. 51 shows mRNA levels for a transgenes encoding anti-CD3 ScFv and CD80 in HCT-116 tumour xenografts 7 or 14-21 days following IV dosing with virus NG-348.

[0150] FIG. 52 shows mRNA levels of MIP1.alpha. and IFN.alpha. transgenes in HCT-116 tumour xenografts 7 or 14-21 days following intravenous dosing with virus NG-347.

[0151] FIG. 53 shows CD80 protein expression in HCT-116 tumour xenografts 7 and 21 days following an intravenous dose of virus NG-348; and shows MIP1.alpha. and CD80 protein expression in HCT-116 tumours following an intravenous dose of virus NG-347.

SUMMARY OF THE SEQUENCE LISTING

TABLE-US-00001

[0152] SEQ ID NO: 1 shows B.sub.Y DNA sequence corresponding to and including bp 29345- 29379 of the EnAd genome. SEQ ID NO: 2 PDGF TM domain SEQ ID NO: 3 SPLICE ACCEPTOR SEQUENCE SEQ ID NO: 4 SPLICE ACCEPTOR SEQUENCE SEQ ID NO: 5 poly adenylation sequence (SV40 late polyA sequence) SEQ ID NO: 6 Internal Ribosome Entry Sequence (IRES) SEQ ID NO: 7 High efficiency self-cleavable P2A peptide sequence SEQ ID NO: 8 High efficiency self-cleavable F2A peptide sequence SEQ ID NO: 9 High efficiency self-cleavable E2A peptide sequence SEQ ID NO: 10 High efficiency self-cleavable T2A peptide sequence SEQ ID NO: 11 Human CD80 amino acid sequence SEQ ID NO: 12 Human Interferona amino acid sequence SEQ ID NO: 13 Human soluble Flt3 ligand amino acid sequence SEQ ID NO: 14 Human Macrophage Inflammatory protein 1a amino acid sequence (LD78b isoform) SEQ ID NO: 15 Membrane anchored form of the anti-human CD3 single chain Fv SEQ ID NO: 16 NG-330 virus genome sequence comprising the EnAd genome with a wtransgene cassette that encodes the T lymphocyte activation antigen, CD 80, inserted in the region B.sub.Y. The transgene cassette contains a 5' SSA, human CD80 cDNA sequence and a 3' poly(A) SEQ ID NO: 17 NG-343 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes IFNa, and CD 80, inserted in the region B.sub.Y. The transgene cassette contains a 5' SSA, IFN.alpha. cDNA sequence, P2A peptide, CD80 cDNA sequence and a 3' poly(A) SEQ ID NO: 18 NG-345 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes Flt3 Ligand, MIP1a and IFN.alpha., inserted in the region B.sub.Y. The transgene cassette contains a 5' SSA, Flt3 Ligand cDNA, P2A peptide sequence, MIP1a cDNA sequence SEQ ID NO: 19 NG-346 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes Flt3 Ligand, MIP1a and CD80, inserted in the region B.sub.Y. The transgene cassette contains a 5' SSA, Flt3 Ligand cDNA sequence, P2A peptide sequence, MIP1a cDNA SEQ ID NO: 20 NG-347 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes IFN.alpha., MIP1a and CD80, inserted in the region B.sub.Y. The transgene cassette contains a 5' SSA, IFN.alpha. cDNA sequence, P2A peptide sequence, MIP1a cDNA sequence, T2A SEQ ID NO: 21 EnAd Genome SEQ ID NO: 22 E2B region of EnAd genome (BP 10355-5068) SEQ ID NO: 23 E3 REGION FROM EnAd SEQ ID NO: 24 A non-coding sequence for inclusion into B.sub.X SEQ ID NO: 25 A non-coding sequence for inclusion into B.sub.Y SEQ ID NO: 26-34 Hinge linker sequences SEQ ID NO: 35-74 Flexible linker sequence SEQ ID NO: 75 & Rigid linker sequence 76 SEQ ID NO: 77-90 Linker sequence SEQ ID NO: 91 PDGFR receptor A SEQ ID NO: 92 PDGFR receptor B SEQ ID NO: 93 Insulin like growth factor 1 SEQ ID NO: 94 IL6-R SEQ ID NO: 95 CD28 SEQ ID NO: 96 NG-348 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes a membrane-anchored chimeric form of the single chain Fv anti-human CD3e and the T lymphocyte activation antigen, CD80 inserted in the region B.sub.Y. SEQ ID NO: 97 Nucleic acid encoding membrane tethered OKT3-scFv SEQ ID NO: 98 Transgene Cassette sequence for NG-348 SEQ ID NO: 99 Membrane anchored form of the anti-human CD3 scFv with C- terminal V5 tag SEQ ID NO: 100 V5 tag (9 amino acid variant) SEQ ID NO: 101 NG-348A virus genome sequence comprising the EnAd genome with a transgene cassette that encodes a membrane-anchored chimeric form of the single chain Fv anti-human CD3e with C-terminal V5 tag and the T lymphocyte activation antigen, CD80 inserted in the region SEQ ID NO: 102 NG-420 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes a membrane-anchored chimeric form of the single chain Fv anti-human CD3e inserted in the region B.sub.Y. The transgene cassette contains a 5' SSA SEQ ID NO: 103 NG-420A virus genome sequence comprising the EnAd genome with a transgene cassette that encodes a membrane-anchored chimeric form of the single chain Fv anti-human CD3e and a C-terminal V5 tag, inserted in the region BY. The transgene cassette contains a SEQ ID NO: 104 Linker SEQ ID NO: 105 Sequence comprising a start codon SEQ ID NO: 106 c-myc tag SEQ ID NO: 107 c-myc tag with amino acid spacer at the N and C-terminal SEQ ID NO: 108 spacer - c-myc tag -spacer PDGF TM domain SEQ ID NO: 109 Fully synthetic EnAd genome with incorporated cloning site for transgene cassette insertion as in plasmid pEnAd2.4

DETAILED DESCRIPTION OF THE DISCLOSURE

[0153] B7 is a family of proteins.

[0154] A B7 protein encoded in an oncolytic viruses of the present disclosure can be useful because the extracellular domain of the protein family member generally modulates a biological function, for example the B7-1 extracellular domain may be employed to prime or stimulate T cells. The actual biological function is specific to the extracellular domain of each given B7 protein (i.e. generally different proteins members of the B7 family have different functions). Other functions of B7 proteins, such as B7-1 and/or B7-2 may include the ability to bind CD28 and/or CTLA-4, and in particular to signal or activate the relevant signaling cascade or cascades.

[0155] In addition or alternatively the transmembrane domain of the B7 proteins can be employed to direct proteins encoded by a virus of the present disclosure to the surface of a cancer cell, for example by fusing the transmembrane domain to the C-terminus of the relevant protein.

[0156] B7 protein as employed herein, unless the context indicates otherwise, refers to the full length sequence of a protein from the B7 family or a sequence at least 95% similar or identical thereto (such as 96%, 97%, 98%, 99% or 100% similar or identical thereto along the entirety of the relevant sequence). The B7 family includes B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, B7-H7. When the full length protein is employed then at least one normal biological function of the protein will generally be present.

[0157] Full length, protein as employed in respect of the B7 family, refers to at least the extracellular domain, including chimeric B7 proteins wherein the sequence of the chimaera has the structure and a function of a B7 protein and wherein the sequences that make up the chimaera are selected from proteins in the B7 family. The elements in a fragment or full length B7 protein may be from the same or different B7 proteins. Thus in one embodiment the B7 fragment or protein is chimeric.

[0158] The chimeric B7 proteins as employed herein refer to where substantially all the sequences making up the chimaera are from a B7 protein, for example at least 98% of the sequence of the chimaera is fragments of B7 proteins fused together. Thus a chimeric fragment as employed herein refers a fragment comprising a sequence from two or more different B7 proteins.

[0159] In one embodiment the full length B7 protein comprises the extracellular domain, for example from a single B7 protein, such as B7-1 and/or B7-2.

[0160] In one embodiment the full length B7 protein comprises the extracellular domain and the transmembrane domain, for example from the same B7 protein or alternatively the extracellular domain from a B7 protein (such as B7-1 and/or B7-2) and a transmembrane domain or equivalent, such as lipid membrane anchor, from a completely different protein.

[0161] In one embodiment a full length chimeric B7 protein may comprise an extracellular domain of one B7 protein (such as B7-1 and/or B7-2) and the transmembrane from a different B7 protein.

[0162] In one embodiment the full length B7 protein comprises the extracellular domain, the transmembrane domain and intracellular domain, for example all from the same B7 protein or from two or more different B7 proteins.

[0163] Active fragment of a B7 protein as employed herein refers to a fragment that has at least one function of a B7 protein, for example to facilitate expression on the cancer cell surface or other biological function of a B7 protein.

[0164] In one embodiment the fragment has at least 50% of the activity of the full-length protein, such as 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the activity of the full-length protein.

[0165] In one embodiment the active fragment comprises or consists of a B7 extracellular domain or a sequence at least 95% similar or identical thereto, such as 96, 97, 98, 99 or 100% similar or identical.

[0166] In one embodiment the B7 fragment comprises or consists of a transmembrane domain from a B7 protein in particular one described herein, such as B7-1. Employing the latter is thought to contribute expression on the cell surface.

[0167] In one embodiment the active B7 fragment may be part of an extracellular domain.

[0168] An active fragment, for example a transmembrane fragment or a larger fragment comprising more B7 domains may be employed in a fusion protein with an additional protein, for example to facilitate expression of the additional protein on the cancer cell surface.

[0169] Larger fragment as employed herein does not refer to size or weight per se but to a larger repertoire of sequence information (i.e. the fragment comprises sequences from at least two B7 domains) which in turn may provide more functionality.

[0170] In one embodiment the larger fragment comprises some biological activity of the relevant B7 protein. In one embodiment an active B7 fragment is a fragment that retains the essential biological activity of the full-length protein, for example the ability to prime or activate T cells.

[0171] The activity of a given protein fragment may be analysed in a relevant in vitro assay, for example using full-length protein as a comparator, for example employing an assay described in the Examples herein. Where the active fragment is a transmembrane domain the activity can be assessed by analysing the surface expression on cells of the relevant protein to which the transmembrane domain is attached, for example using an assay described in the Examples herein.

[0172] When the full-length B7 protein is part of a fusion protein then the B7 portion may be linked to the additional protein by an amide bond between the end of one sequence and the beginning of the next protein sequence or connected by a linker. Examples of linkers are given below.

[0173] A full length B7 protein comprising a transmembrane domain can be employed to present the extracellular domain of the B7 protein and the protein or fragment fused or linked thereto on the surface of the infected cancer cell. Generally in this embodiment the B7 protein will be attached to the surface of the cancer cell and the "other" protein will be at the N-terminus and on the extracellular side of the cancer cell surface.

[0174] Having said that the proteins can be arrange as desired, for example with the B7 extracellular domain at the N-terminal, fused or linked at its C-terminal to the next protein or fragment, which in turn is fused or linked at the C-terminal to the transmembrane domain, for example a transmembrane domain from a B7 protein.

[0175] Generally when a full-length B7 protein is employed in a fusion protein then both the B7 protein and the additional protein will have a biological function.

[0176] Fusion protein as employed herein refers to at least two proteins or fragments or a combination of at least one protein and at least one fragment fused directly or connected to each other, for example by a linker.

[0177] Fused as employed herein generally refers to an amide bond between the end of one polypeptide (or protein/fragment) and the beginning of the next polypeptide (or protein/fragment).

[0178] Linked, unless the context indicates otherwise, refers to wherein two entities, such as two polypeptide sequences are connected via a linker. A linker is a sequence which is not naturally present in either polypeptide or a sequence, which is not present in that particular position relative to both polypeptides.

[0179] In one embodiment the fusion protein comprises a B7 protein or an active fragment thereof. Fusion proteins comprising B7 fragments or protein and additional proteins are not referred to as chimeric proteins herein. Generally fusion protein as employed herein refers to a combination of a B7 protein or fragment thereof and another non-B7-protein/fragment.

[0180] Only proteins containing fragments from different B7 proteins are referred to as chimeric herein, as described supra.

[0181] In one embodiment fusion proteins of the present disclosure do not comprise a B7 protein or active fragment thereof and are encoded by a virus of the present disclosure in addition to the B7 protein or fragment thereof.

[0182] Thus viruses of the present disclosure may encode entities in addition to the B7 protein or active fragment thereof, such entities include further proteins.

B7 Family

[0183] In one embodiment the B7 is independently selected from B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, B7-H7, active fragments of the same, and combinations thereof. In one embodiment the B7 protein is B7-1 (CD80), B7-2 (CD86) or an active fragment of any of the same and combinations thereof, in particular B7-1 or an active fragment thereof.

[0184] B7 proteins include B7-1(also known as CD80 uniprot number P33681), B7-2 (also known as CD86 uniprot number P42081). These proteins bind CD28 and CTLA-4.

[0185] In one embodiment CD80 has the following sequence:

TABLE-US-00002 SEQ ID NO: 11 MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLS CGHNVSVEELAQTRIYWQKEKKMVLTMMSGDMNIWPEYKNRTIFDITNN LSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKADFPTPSI SDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETE LYAVSSKLDFNMTTNHSFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLP SWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRESVRPV

[0186] Other B7 proteins include B7-DC (also known as PDCD1LG2 and PD-L2 uniprot number Q9BQ51), B7-H1 (also known as PD-L1 and CD274: Uniprot number Q9NZQ7). Both these proteins bind PD-1.

[0187] Programmed death-ligand 1 (PD-L1) is a 40 kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the immune system. It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. Ovarian cancer patients with higher expression of PD-L1 had a significantly poorer prognosis than those with lower expression. PD-L1 expression correlated inversely with intraepithelial CD8+ T-lymphocyte count, suggesting that PD-L1 on tumor cells may suppress antitumor CD8+ T cells. The effect might be tumor type dependent; a study on patients with non-small cell lung cancer showed that greater PD-L1 protein and mRNA expression is associated with increased local lymphocytic infiltrate and longer survival. A number of anti-PDL1 antibodies have been shown to be of interest for treating several cancers in clinical trials.

[0188] In one embodiment the B7-DC and/or B7-H1 protein or fragment thereof employed in the virus of the present disclosure does not stimulate immune suppression, for example is mutated to remove the immune suppressive function.

[0189] Alternatively, a virus encoding B7-H1 extracellular domain in an unmutated form may be employed to treat appropriate cancers, where upregulation of PD-L1 is associated with a good/improved prognosis, such as lung cancer.

[0190] In one embodiment at least the cytoplasmic (intracellular domain) of B7-DC and/or B7-H1 is deleted or non-functional. Whilst not wishing to be bound by theory there is evidence to suggest that removal of the intracellular domain reduces the cancer cells resistance to lysis Blood 2008, Apr. 1; 111(7) 3635-3643.

[0191] In one embodiment only the transmembrane domain fragment of B7-DC and/or B7-H1 is employed. In one embodiment the following proteins are not provided as full-length proteins B7-DC and B7-H1 with a relevant biological activity.

[0192] Other B7 proteins include B7-H2 (also known as ICOSLG, B7RP1, CD275: Uniprot number 075144) which binds ICOS, B7-H3 (also known as CD276: Uniprot number Q5ZPR3), B7-H4 (also known as VTCN1: Uniprot number Q727D3), B7-H5 (also known as VISTA, Platelet receptor Gi24, SISP1), B7-H6 (also known as NCR3LG1, NR3L1) which binds NKp30, B7-H7 (also known as HHLA2) which binds CD28H.

[0193] In one embodiment the fragment only comprises the transmembrane domain of any one B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7.

[0194] Individual proteins include single proteins, that is proteins or active fragments thereof that are not part of a fusion protein (including chimeric proteins), and also fusion proteins. In one embodiment the individual proteins are single proteins (including active fragments thereof).

[0195] In one embodiment the cytoplasmic domain of the B7 protein is present. In one embodiment the cytoplasmic domain is absent. The absence of the cytoplasmic domain may reduce or eliminate intracellular signaling to the cancer cell, which is relevant to one or more embodiments discussed below.

"Transmembrane Domains"

[0196] In one embodiment a transmembrane domain other than one derived from a B7 protein is employed to express a protein (including a fusion protein) encoded by a virus of the present disclosure on the surface of an infected cancer cell, for example the transmembrane domain can be employed to present an active B7 protein fragment or another protein of interest on the surface of the infected cancer cell. Alternatively it can be employed to present a fusion protein, for example comprising a B7 protein or active fragment thereof on said surface. In one embodiment the transmembrane domain from a PDGF receptor or fragment thereof is employed to express a B7 and/or another protein on the cancer cell surface.

[0197] In one embodiment a transmembrane tether or anchor sequence employed in the present disclosure comprises a PDGFR TM domain (e.g. ala513-arg561), such as AVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKPR (SEQ ID NO: 2).

[0198] In one embodiment a tether or anchor sequence employed in the present disclosure comprises a tag attached, for example to a PDGF receptor or fragment thereof, such as PDGFR TM domain, in particular SEQ ID NO: 2.

[0199] Suitable tags include His-tags, Flag-tags, c-myc tag and the like. More specifically the tether or anchor may comprise a c-myc tag eg. of SEQ ID NO: 106 EQKLISEEDL followed by a PDGFR TM domain is employed, (for example ala513-arg561), such as shown in SEQ ID NO: 2 AVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKKPR.

[0200] In one embodiment the c-myc tag comprises a spacer or spacer amino acids at the 3' and/or 5' end, for example gsEQKLISEEDLn (SEQ ID NO: 107 wherein the lower case letters represent the amino acids which are added to the tag as spacers).

[0201] In one embodiment the tether or anchor sequence employed is gsEQKLISEEDLnAVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKKPR (SEQ ID NO: 108) wherein the lower case letter represent amino acid spacers).

[0202] Generally the protein/polypeptide to which the tether or anchor is attached does not comprise a stop codon.

[0203] An exogenous protein or proteins encoded by the virus according to the present disclosure will generally comprise a leader sequence (also referred to as a signal peptide).

[0204] A leader sequence is, for example a sequence about 5 to 30 amino acids long located at the N-terminal of the protein or polypeptide.

[0205] In one embodiment the leader sequence for the protein to be expressed on the cancer cell surface is human, for example HuVHSS.

[0206] In one embodiment the structure of the ORF cassette is as follows:

LS-POLY-TAG-TM_D

wherein

[0207] LS is a leader sequence, for example a human leader sequence;

[0208] POLY is a polynucleotide encoding polypeptide or proteins of interest, in particular one disclosed herein;

[0209] TAG is a tag for example one disclosed herein, such as c-myc, in particular SEQ ID NO: 100 or 106;

[0210] TM_D is a TM domain for example a PDGFR TM domain, for example SEQ ID NO: 2. When the polypeptide is a scFv then the ORF may be as follows:

[0210] LS-VAR.sub.1-LINK-VAR.sub.2-TAG-TM_D

wherein LS is a leader sequence, for example a human leader sequence;

[0211] VAR1 is a polynucleotide encoding a variable region such as VH region;

[0212] LINK is a linker, for example as disclosed herein, such as a linker based on the units of G4S, in particular SEQ ID NO: 104 GGGGSGGGGSGGGGS;

[0213] VAR2 is a polynucleotide encoding a variable region, such as a VL region;

[0214] TAG is a tag, for example one disclosed herein, such as c-myc, in particular SEQ ID NO: 100 or 106;

[0215] TM_D is a TM domain for example a PDGFR TM domain, for example SEQ ID NO: 2.

[0216] The disclosure also extends to embodiments, in particular those described specifically herein, which comprise a tag at the N- or C-termini of the polypeptide chains, such that it resides inside or on the outside of the membrane. Thus a C-termini tag located inside the membrane is advantageous because it is not likely to interfere with the binding or function of the polypeptide.

[0217] Having said this expressing the tag on the N-terminal of a surface expressed protein may be useful in some situations because may facilitate isolation, identification and purification of cells expressing the protein.

[0218] In one embodiment a combination of a transmembrane domain and a secretory signal sequence is employed to express a protein encoded by the virus (for example as described herein) on the surface of an infected cancer cell. The present inventors have shown that the proteins encoded are expressed only on cells which are permissive to infection by the oncolytic virus, i.e. cancer cells.

[0219] In one embodiment the fragment employed to express the protein on the surface of the infected cancer cell (such as the transmembrane fragment) is selected from about 20 to 25 hydrophobic amino acids which form a transmembrane alpha helix, for example from the proteins including PDGF receptor, insulin-like growth factor receptor, IL-6 receptor, CD28, glycophorin, LDL receptor, influenza HA protein, insulin receptor, Asialoglycoprotein receptor, Transferrin receptor.

[0220] In one embodiment the fragment employed to express the protein on the surface of the infected cancer cell (such as the transmembrane fragment) is selected from the group comprising TM domain sequences (minimal portions) given in SEQ ID NO: 91, 92, 93, 94 or 95:

TABLE-US-00003 SEQ ID NO: Name SEQUENCE 91 PDGFR Receptor AVLVLLVIVIISLIVLVVIW A 92 PDGFR Receptor VVISAILALVVLTIISLIILI B 93 INSULIN-LIKE IIIGPPLIFVFLFSVVIGSIYLFL GROWTH FACTOR 1 94 IL6-R SSSVPLPTFLVAGGSLAFGTLLCIAIVL 95 CD28 FWVLVVVGGVLACYSLLVTVAFIIFWV

[0221] In one embodiment the transmembrane domain employed is derived from a G protein-coupled receptor or S antigen from hepatitis B.

[0222] In one embodiment a fusion protein comprising a full length extracellular domain of a B7 protein or fragment and also a transmembrane domain derived from a protein other than B7 is arranged such that the B7 protein is located at the terminal end of the fusion protein distal from the cancer cell surface, that is on the outside of the cancer cell facing the extracellular space.

[0223] Viruses

[0224] Having the DNA sequence encoding a B7 protein or an active fragment under the control of an endogenous promoter is also advantageous because the protein is expressed in accordance with the virus life cycle as opposed to being constitutively expressed. In the present situation continuous expression under an exogenous promoter, for example a strong promoter like the CMV promoter, may produce more B7 protein than is necessary for a therapeutic effect and may result in off-target effects.

[0225] Alternatives to transmembrane domains for expressing proteins on the surface of the infected cancer cell include approaches employing glycophospholipid anchor (also referred to as a GPI anchor) attached to the C-terminal amino acid of the extracellular protein or fragment (Low et al 1986, Cross 1987, Low and Saltiel 1988, Ferguson and William 1988). Suitable glycophospholipid anchors, for use in the present disclosure include those from Thy-1, N-CAM and DAF.

[0226] In one embodiment oncolytic virus according to present disclosure is an adenovirus, for example a group B adenovirus. In one embodiment the virus according to the present disclosure is a chimeric virus, for example EnAd. In one embodiment the adenovirus is replication competent.

[0227] In one embodiment the virus is replication deficient and provided as a viral vector.

[0228] In one embodiment the sequence encoding the B7 protein or active fragment thereof is located between the stop codon and polyA recognition site of the adenoviral gene L5 and the stop codon and polyA recognition site of the gene E4.

[0229] In one embodiment the sequence encoding the B7 protein or active fragment thereof is located between about bp 29356 and about 29357 of the EnAd genome, for example as shown in SEQ ID NO: 21, or a position equivalent thereto. The skilled person will understand that the absolute numerical value of the location can change based on how the numbering is allocated. However, the relative position of the inserted gene remains the same irrespective of the absolute numerical values employed.

[0230] In one embodiment the oncolytic adenovirus according to the present disclosure has a formula (I):

5'ITR--B.sub.1-B.sub.A-B.sub.2-B.sub.X-B.sub.B-B.sub.Y-B.sub.3-3'ITR (I)

wherein:

[0231] B.sub.1 is a bond or comprises: E1A, E1B or E1A-E1B (in particular E1A, E1B or E1A-E1B);

[0232] B.sub.A is E2B-L1-L2-L3-E2A-L4;

[0233] B.sub.2 is a bond or comprises E3 or a transgene, for example under an endogenous or exogenous promoter;

[0234] B.sub.X is a bond or a DNA sequence comprising: a restriction site, one or more transgenes or both;

[0235] B.sub.B comprises L5;

[0236] B.sub.Y comprises a transgene encoding a B7 protein or an active fragment thereof; and

[0237] B.sub.3 is a bond or comprises E4.

[0238] In one embodiment the oncolytic virus has a formula (Ia):

5'ITR-B.sub.1-B.sub.A-B.sub.2-B.sub.B-B.sub.Y-B.sub.3-3'ITR (Ia)

wherein:

[0239] B.sub.1 is a bond or comprises: E1A, E1B or E1A-E1B (in particular E1A, E1B or E1A-E1B);

[0240] B.sub.A is E2B-L1-L2-L3-E2A-L4;

[0241] B.sub.2 is a bond or comprises E3;

[0242] B.sub.B comprises L5;

[0243] B.sub.Y comprises a transgene encoding a B7 protein or an active fragment thereof; and

[0244] B.sub.3 is a bond or comprises E4.

[0245] In one embodiment the virus genome in constructs of formula (I) and/or (Ia) is from Ad11 or EnAd, in particular EnAd.

[0246] In one embodiment the transgene encoding the B7 protein or active fragment thereof, is under the control of an endogenous promoter, for example the major late promoter.

Regulatory Elements

[0247] In one embodiment B.sub.Y comprises a transgene cassette, said cassette comprising a transgene encoding a B7 protein or fragment thereof and a regulatory element, such as combination of regulatory elements.

[0248] In one embodiment the regulatory element is splice acceptor sequence.

[0249] In one embodiment the regulatory element is a Kozak sequence.

[0250] In one embodiment, for example where the transgene encodes a polycistronic RNA molecule, the regulatory element is an IRES sequence.

[0251] In one embodiment the regulatory sequence is a high efficiency self-cleavable peptide sequence such as P2A, T2A, F2A, E2A.

[0252] In one embodiment the regulatory sequence is a polyA tail.

[0253] In one embodiment there are at least two regulatory sequences, for example a splice acceptor and a Kozak sequence or a splice acceptor and a polyA tail, or a splice acceptor and an IRES sequence, or a splice acceptor and a P2A sequence.

[0254] In one embodiment there are at least three regulator sequences, for example a splice acceptor sequence, a Kozak sequence and polyA tail, or a splice acceptor sequence an IRES or 2A sequence and a polyA tail; or a splice acceptor sequence, Kozak sequence and an IRES or 2A sequence.

[0255] In one embodiment there are at least four regulatory sequences, for example a splice acceptor sequence, a Kozak sequence, an IRES or 2A sequence and a polyA tail, in particular located between L5 and E4 in the order splice acceptor sequence, Kozak sequence, IRES or 2A sequence and a polyA tail.

[0256] In one embodiment the transgene encodes a polycistronic RNA molecule comprising both an IRES and a 2A regulatory sequence.

Proteins Encoded B.sub.Y the Virus

[0257] In one embodiment the virus of the present disclosure encodes multiple proteins for expression on the surface of the infected cancer cell wherein at least one is a B7 protein or an active fragment thereof, for example two, three, four or more different proteins are encoded, in particular two or three proteins are encoded by the virus for expression on the cancer cell surface or secretion into the extracellular space. Protein in this context includes a fusion protein. In one embodiment the virus of the present disclosure encodes two different B7 proteins, active fragments thereof or combinations of the same, for example both for expression on a cancer cell surface.

[0258] In one embodiment the virus according to the present disclosure encodes one or two protein for cell surface expression and one or two proteins which are not capable of being anchored on the cell surface, for example are intended to act with the cancer cell or are for secretion/release from the cells.

[0259] In one embodiment a B7 protein or active fragment is encoded by the virus of the present disclosure for expression on the surface of the cancer cell and a soluble form, which is released or secreted from the cell, of the same B7 protein or a different B7 protein (including active fragments) is also encoded by the virus.

[0260] In one embodiment at least two different B7 proteins or active fragments are encoded by a virus of the present disclosure.

[0261] In one embodiment at least one protein expressed on the cell surface is a B7 protein and at least one non-cell-anchored (e.g. secreted) proteins is a non-B7 protein.

[0262] In one embodiment the multiple proteins may be encoded to be expressed as separate proteins which are independently processed and expressed in the cancer cell membrane. The independence of the proteins on the surface of the cancer cell may make a positive contribution to the immune activation. Whilst not wishing to be bound by theory, lipid packing can influence the fluidity (i.e. the viscosity) of the lipid bilayer in the membrane of the cancer cell. Viscosity of the membrane can affect the rotation and orientation of proteins and other bio-molecules within the membrane, thereby affecting the functions of these molecules. Thus when the proteins encoded by the virus are located as individual and separate proteins within the membrane of the infected cancer cell, the fluidity of the lipid bilayer allows independent movement of the molecules which may be a particularly suitable format, for example similar to a natural format that is conducive to biological function.

[0263] In one embodiment the independently processed and expressed proteins are located (anchored) in different locations, such as physically separate locations, in the cancer cell membrane.

[0264] In one embodiment one or more proteins (for example all the proteins) encoded by the virus and expressed on the surface of the infected cancer cell are not fusion proteins.

[0265] As described supra in some embodiment the proteins are expressed as a fusion protein.

[0266] In one embodiment the virus of the present disclosure provides one or more separate independent proteins for cell surface expression and one or more fusion proteins for cell surface expression.

[0267] Thus in one embodiment the virus according to the present disclosure comprises DNA sequences encoding said multiple proteins for expression, for example on the surface or the infected cancer cell.

[0268] Thus in one embodiment the virus according to the present disclosure comprises two or more transgenes, in the same or different locations in the virus genome. When located at the same position in the virus genome the multiple proteins will still be expressed independently at the surface of the cancer cell.

[0269] In one embodiment the multiple proteins (including fusion proteins) are encoded in different locations in the virus genome, for example in E3, B.sub.X and/or B.sub.Y and are expressed separately on the surface of the infected cancer cell.

[0270] In one embodiment the multiple proteins (including fusion proteins) are encoded in the same location in the virus genome and expressed together on the infected cancer cell surface, for example where the proteins encoded are provided as a fusion protein, in particular wherein the fusion protein comprises a B7 protein or an active fragment thereof.

[0271] In one embodiment the B7 protein in the fusion protein is a full length protein, in particular a protein described herein, such as B7-1 and/or B7-2, fused or linked to another protein of interest or an active fragment thereof. In one embodiment, the fusion protein comprises a transmembrane from a B7 protein. In one embodiment the B7 is an active fragment excluding the transmembrane domain. In the latter embodiment a transmembrane other than one derived from a B7 protein may be employed to ensure the fusion protein is presented on the surface of the infected cancer cell.

[0272] In one embodiment the multiple proteins are encoded in the same location in the virus and are expressed as one or more fusion proteins together on the surface of the infected cancer cell.

[0273] When the location of the gene(s) encoding a protein or protein(s) of interest in the virus is the same then the genes may, for example be linked by an IRES sequence or a 2A peptide.

[0274] In one embodiment the virus according to the present disclosure comprises a "second" transgene and optionally a third transgene (i.e. one or more of said multiple proteins, for example encoding a polypeptide selected from the group comprising a cytokine, a chemokine, a ligand, and an antibody molecule, such as an antagonistic antibody molecule, and an agonistic antibody molecule.

[0275] In one embodiment the additional protein or proteins is/are independently selected from the group comprising an antibody, antibody fragment or protein ligand that binds CD3, CD28, CD80, CD86, 4-1BB, GITR, OX40, CD27, CD40 and combinations, for example in forms suitable for expression on the surface of a cancer cell.

[0276] In one embodiment the additional protein is an anti-CD3 antibody, for example independently selected from a Muromonab-CD3 (also known as OKT3), otelixizumab (also known as TRX4), teplizumab (also known as hOKT3.gamma.1(Ala-Ala)), or visilizumab.

[0277] In one embodiment the anti-CD3 antibody is in the form of an antibody fragment, for example an scFv that is part of a fusion protein with the transmembrane region of another protein, for example the transmembrane domain from the PDGF receptor or from the cell surface form of IgG

[0278] In one embodiment an antibody molecule is an inhibitor (antagonistic antibody) is independently selected from the group comprising an inhibitor of an angiogenesis factor, such as an anti-VEGF antibody molecule, and inhibitor of T cell deactivation factors, such as an anti-CTLA-4, anti-PD1 or anti-PDL1 antibody molecule. In one embodiment antibody molecule is an agonist independently selected from the group comprising antibodies to CD40, GITR, OX40, CD27 and 4-1B.sub.B.

[0279] In one embodiment an additional transgene encodes a cytokine, or soluble variant thereof selected from the group comprising IL-2, IFN.alpha., IFN.beta., IFN.gamma., GM-CSF, IL-15, IL-12 and fins-related tyrosine kinase 3 ligand (FLT3L). Advantageously, one or more of this group of proteins expressed by the virus, in particular as a free protein secreted from the cancer cell, may be particularly suitable for stimulating an immune response in vivo to the cancer cell.

[0280] In one embodiment an additional transgene encodes a chemokine, selected from the group comprising MIP1-alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21. Advantageously, one or more of this group of proteins is expressed by the virus as a free protein which may be secreted from the cancer cell may be particularly suitable for attracting immune cells and stimulating an immune response to the cancer cell in vivo.

[0281] In one embodiment in addition to at least the B7 protein or active fragment thereof expressed on the surface of the infected cancer cell, one or more molecules are also expressed on the surface and/or secreted.

[0282] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof.

[0283] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and an anti-CD3 (agonist) antibody or antibody binding fragment (such as a scFv) also for expression on the cancer cell surface, in particular where the proteins are expressed as individual proteins on the cell surface.

[0284] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and an anti-VEGF (antagonist) antibody or a binding fragment thereof also for expression on the cancer cell surface or for release from the cancer cell, for example by secretion or after lysis/death of the infected cancer cell.

[0285] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and an antibody, antibody fragment or protein ligand that binds CD3, CD28, CD80, CD86, 4-1BB, GITR, OX40, CD27, CD40 also for expression on the cancer cell surface or for release from the cancer cell, for example by secretion or release after lysis/death of the infected cancer cell.

[0286] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and a cytokine selected from IL-2, IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, IL-15, IL-12, and FLT3L, for example for release from the cancer cell, in particular by secretion or release after cell lysis/death of the infected cancer cell.

[0287] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and a chemokine selected from MIP1-alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21, for example for release from the cancer cell, in particular by secretion or release after cell lysis/death of the infected cancer cell.

[0288] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and an anti-CD3 (agonist) antibody or antibody binding fragment (such as a scFv) also for expression on the cancer cell surface (in particular where the proteins are expressed as individual proteins on the cell surface) and further encodes a cytokine or chemokine selected from IL-2, IFN-alpha, IFN-gamma, GM-CSF, IL-15, IL-12, FLT3L, MIP1-alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21 for example for release from the cancer cell, in particular by secretion or after cell lysis/death of the infected cancer cell.

[0289] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and an anti-CD3 (agonist) antibody or antibody fragment (such as a scFv) also for expression on the cancer cell surface (in particular where the proteins are expressed as individual proteins on the cell surface) and further encodes an antibody, antibody fragment or protein ligand that binds CD28, CD80, CD86, 4-1B.sub.B, GITR, OX40, CD27, CD40 or an anti-VEGF (antagonist) antibody also for expression on the cancer cell surface or for release from the cancer cell, for example by secretion or release after lysis/death of the infected cancer cell.

[0290] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and two different cytokines or chemokines selected from IL-2, IFN.alpha., IFN.beta., IFN.gamma., GM-CSF, IL-15, and IL-12, FLT3L, MIP1.alpha., IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21, for example for release from the cancer cell, in particular by secretion of after cell lysis/death of the infected cancer cell.

[0291] Thus in one embodiment the virus encodes B7-1, B7-2 or an active fragment of any one of the same or a combination thereof for expression on the surface of the infected cancer cell and an anti-CD3 (agonist) antibody or antibody binding fragment (such as a scFv) also for expression on the cancer cell surface (in particular where the proteins are expressed as individual proteins on the cell surface) and further encodes a cytokine independently selected from IL-2, IFN.alpha., IFN.gamma., GM-CSF, IL-15, and IL-12, and or a chemokine selected from RANTES (CCL5), MIP1.alpha. (LD78a (CCL3) or LD78s (CCL3L1) isoforms), MIP1.beta. which can be released from the cancer cell, in particular by secretion before and release after cell lysis/death of the infected cancer cell.

[0292] In one embodiment which in particular may be combined with any of the embodiments above the virus further encodes an anti-PD-1 antibody (an antagonist).

[0293] In one embodiment the protein or proteins encoded in the transgene cassette for cell membrane expression may also comprise a peptide linker or spacer between the transmembrane domain and the extracellular ligand binding domain. Such linkers or spacers may add flexibility to the cell surface expressed protein that enhances the ability of the protein to interact with its target molecule, for example on an adjacent cell. Such linkers or spacers may also be designed or selected to promote dimerisation or trimerisation of the proteins at the cell surface, via disulphide bond formation or protein-protein interactions.

[0294] For example the hinge regions of immunoglobulin molecules or CD8 may be employed to enhance both flexibility and dimerisation In one embodiment the protein or proteins encoded in the transgene cassette may also comprise a peptide tag. The peptide tag may include c-myc, poly-histidine, V5 or FLAG tags and can be located on the N-terminus or C-terminus of the polypeptide, either intracellularly or extracellularly, or may be encoded within the protein for example in an extracellular loop or between the transmembrane domain and the extracellular domain. Peptide tags can be used as spacers or linkers between different protein domains, for example the transmembrane and the extracellular domain, and can be used for detection or purification or detection of the protein, or cells expressing the protein.

[0295] In one embodiment the one or more additional transgenes (other than the gene encoding the B7 protein or fragment thereof) is under the control of an exogenous or endogenous promoter, for example an endogenous promoter. In one embodiment a transgene in the E3 region (B.sub.2) is under control of an exogenous promoter.

[0296] In one embodiment the one or more additional transgenes genes are between the E3 region and the fibre L5 in the adenovirus genome, for example at a position B.sub.X in the construct of formula (I), in particular under the control of an exogenous promoter. thus in one embodiment a transgene in B.sub.X is under the control of an exogenous.

[0297] In one embodiment the one or more additional transgenes genes are between the E4 region and the fibre L5 in the adenovirus genome, for example at a position B.sub.Y in the construct of formula (I) or (Ia), in particular under the control of an endogenous promoter, such as the major late promoter. This may be in addition to the B7 protein or active fragment thereof encoded in the region B.sub.Y.

[0298] In one embodiment there is provided a composition comprising an oncolytic adenovirus according to the present disclosure, for example a pharmaceutical composition, in particular comprising a pharmaceutically acceptable excipient, such as a diluent or carrier.

[0299] In one embodiment there is provided an oncolytic adenovirus according to the present disclosure or a composition comprising the same, for use in treatment, in particular for use in the treatment of cancer.

[0300] In one embodiment there is provided a method of treating a patient in need thereof comprising administering a therapeutically effective amount of an oncolytic virus according to the present disclosure or a composition, such as a pharmaceutical composition comprising the same.

[0301] In one embodiment there is provided use of an oncolytic adenovirus according to the present disclosure or a composition comprising the same for the manufacture of a medicament for the treatment of cancer, in particular carcinomas, for example colorectal, lung, bladder, renal, pancreatic, hepatic, head and neck, breast or ovarian cancer.

[0302] In one embodiment there is provided a polynucleotide comprising a genomic sequence of at least 50% of a virus according to the present disclosure (for example 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%) and comprising a sequence encoding a B7 protein or an active fragment thereof, for example a B7 protein disclosed herein, such as B7-1 or an active fragment thereof. In one embodiment the polynucleotide sequence is in the form of a plasmid.

[0303] In one embodiment there is provided a host cell, for example a mammalian cell, such as a HEK293 cell or a derivative thereof, comprising an oncolytic virus according to the present disclosure or a polynucleotide sequence according to the present disclosure.

[0304] In one embodiment there is provided a process for preparing an oncolytic adenovirus according to the present disclosure comprising a step of inserting a polynucleotide encoding B7 protein or an active fragment thereof into an oncolytic adenovirus.

[0305] In one embodiment there is provided a process of replicating a virus according to the present disclosure comprising the step of culture host cells in the presence of the virus under conditions suitable for replication. Generally the method will comprise a further step of harvesting the virus, for example from the supernatant or after lysis of the host cells.

Definitions

[0306] Oncolytic virus with selectivity for cancer cells as employed herein refers to a virus that preferentially kills cancer cells, for example because it preferentially infects cancer cells and/or the virus life cycle is dependent on a gene, such as p53 that is disregulated, for example over-expressed in cancer cells. In one embodiment the oncolytic virus preferentially infects cancer cells and goes on to replicate its genome and produce capsid proteins to generate new virus particles, for example as per EnAd.

[0307] The selectivity for cancer cells (therapeutic index) can be tested as described in WO2005/118825 incorporated herein by reference.

[0308] Transgene as employed herein refers to a gene that has been inserted into the genome sequence of the adenovirus, wherein the gene is unnatural to the virus (exogenous) or not normally found in that particular location in the virus. Examples of transgenes are given herein. Transgene as employed herein also includes a functional fragment of the gene that is a portion of the gene which when inserted is suitable to perform the function or most of the function of the full-length gene, for example 50% of the function or more.

[0309] Transgene and coding sequence are used interchangeably herein in the context of inserts into the viral genome, unless the context indicates otherwise. Coding sequence as employed herein means, for example a DNA sequence encoding a functional RNA, peptide, polypeptide or protein. Typically the coding sequence is cDNA for the transgene that encodes the functional RNA, peptide, polypeptide or protein of interest. Functional RNA, peptides, polypeptide and proteins of interest are described below.

[0310] In one embodiment transgene as employed herein refers to a segment of DNA containing a gene or cDNA sequence that has been isolated from one organism and is introduced into a different organism i.e. the virus of the present disclosure. In one embodiment this non-native segment of DNA will generally retain the ability to produce functional RNA, peptide, polypeptide or protein. Transgenes employed may for example encode a single proteins or active fragment thereof, chimeric protein or a fusion protein.

[0311] Clearly the virus genome contains coding sequences of DNA. Endogenous (naturally occurring genes) in the genomic sequence of the virus are not considered a transgene, within the context of the present specification unless then have been modified by recombinant techniques such as that they are in a non-natural location or in a non-natural environment.

[0312] Thus in one embodiment the transgene inserted encodes a human or humanised protein, polypeptide or peptide.

[0313] In one embodiment the transgene comprises a DNA sequence encoding a B7 protein or an active fragment thereof. The present disclosure provides that the B7 protein or activate fragment thereof may be provided in one or more formats independently selected from a fusion protein, a simple B7 protein or an active fragment thereof.

[0314] Simple B7 protein or an active fragment thereof as employed herein refers to proteins which are essentially wild-type proteins, for example which are not part of a fusion protein and which has a sequence identical or similar to the relevant known protein, in particular the known human protein. Simple gene also includes wherein 10% of the amino acids are substituted or deleted over the whole length of the relevant protein.

[0315] GPI anchor as employed herein refers to is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification. It is composed of a phosphatidylinositol group linked through a carbohydrate-containing linker (glucosamine and mannose glycosidically bound to the inositol residue) and via an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein. The two fatty acids within the hydrophobic phosphatidyl-inositol group anchor the protein to the cell membrane.

[0316] Glypiated (GPI-linked) proteins generally contain a signal peptide, thus directing them into the endoplasmic reticulum (ER). The C-terminus is composed of hydrophobic amino acids that stay inserted in the ER membrane. The hydrophobic end is then cleaved off and replaced by the GPI-anchor. As the protein progresses through the secretory pathway, it is transferred via vesicles to the Golgi apparatus and finally to the extracellular space where it remains attached to the exterior leaflet of the cell membrane. Since the glypiation is the sole means of attachment of such proteins to the membrane, cleavage of the group by phospholipases will result in controlled release of the protein from the membrane. The latter mechanism is used in vitro; i.e., the membrane proteins released from the membranes in the enzymatic assay are glypiated protein.

[0317] Phospholipase C (PLC) is an enzyme that is known to cleave the phospho-glycerol bond found in GPI-anchored proteins. Treatment with PLC will cause release of GPI-linked proteins from the outer cell membrane. The T-cell marker Thy-1 and acetylcholinesterase, as well as both intestinal and placental alkaline phosphatases, are known to be GPI-linked and are released by treatment with PLC. GPI-linked proteins are thought to be preferentially located in lipid rafts, suggesting a high level of organization within plasma membrane microdomains.

[0318] A review of GPI anchors written by Ferguson, Kinoshita and Hart is available in Chapter 11 of Essentials of Glycobiology 2nd Edition.

Viruses

[0319] Replication competent in the context of the present specification refers to a virus that possesses all the necessary machinery to replicate in cells in vitro and in vivo, i.e. without the assistance of a packaging cell line. A viral vector, for example deleted in at least the E1A region, capable of replicating in a complementary packaging cell line is not a replication competent virus in the present context.

[0320] A viral vector is a replication deficient virus, which requires a packaging cell line (comprising a transgene) to replicate.

[0321] A replication capable virus as employed herein refers to a replication competent virus or a virus whose replication is dependent on a factor in the cancer cells, for example an upregulated factor, such as p53 or similar.

[0322] In one embodiment the adenovirus is a human adenovirus. "Adenovirus", "serotype" or adenoviral serotype" as employed herein refers to any adenovirus that can be assigned to any of the over 50 currently known adenoviral serotypes, which are classified into subgroups A-F, and further extends to any, as yet, unidentified or unclassified adenoviral serotypes. See, for example, Strauss, "Adenovirus infections in humans," in The Adenoviruses, Ginsberg, ea., Plenum Press, New York, N.Y., pp. 451-596 (1984) and Shenk, "Adenoviridae: The Viruses and Their Replication," in Fields Virology, Vol. 2, Fourth Edition, Knipe, 35 ea. Lippincott Williams & Wilkins, pp. 2265-2267 (2001) as shown in Table 1.

TABLE-US-00004 SubGroup Adenoviral Serotype A 12, 18, 31 B 3, 7, 11, 14, 16, 21, 34, 35, 51 C 1, 2, 5, 6 D 8-10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36- E 4 F 40, 41

[0323] Adenoviruses are grouped based on their capsid.

[0324] In one embodiment the adenovirus is a subgroup B, for example independently selected from the group comprising or consisting of: Ad3, Ad7, Ad11, Ad14, Ad16, Ad21, Ad34 and Ad51, such as Ad11, in particular Ad11p (the Slobitski strain). In one embodiment the adenovirus of the invention has the capsid, such as the hexon and/or fibre of a subgroup B adenovirus, such as Ad11, in particular Ad11p. In one embodiment the adenovirus is Ad11 or has the fibre and/or hexon and/or penton of Ad1, such as Ad11p.

[0325] In one embodiment the virus of the present disclosure is not a group A virus.

[0326] In one embodiment the virus of the present disclsoure does not comprise an adeno death protein (ADP).

[0327] In one embodiment the virus of the present disclosure is not a group C virus.

[0328] In one embodiment the virus of the present disclosure does not comprise more and a fragment of part of an Ad5 virus.

[0329] Enadenotucirev (EnAd) is a chimeric oncolytic adenovirus, formerly known as ColoAd1 (WO2005/118825), with fibre, penton and hexon from Ad11p, hence it is a subgroup B virus. It has a chimeric E2B region, which comprises DNA from Ad11p and Ad3. Almost all of the E3 region and part of the E4 region is deleted in EnAd. Therefore, it has significant space in the genome to accommodate additional genetic material whilst remaining viable. Furthermore, because EnAd is a subgroup B adenovirus, pre-existing immunity in humans is less common than, for example, Ad5. Other examples of chimeric oncolytic viruses with Ad1 fibre, penton and hexon include OvAd1 and OvAd2 (see WO2006/060314).

[0330] EnAd seems to preferentially infect tumour cells, replicates rapidly in these cells and causes cell lysis. This, in turn, can generate inflammatory immune responses thereby stimulating the body to also fight the cancer. Part of the success of EnAd is hypothesised to be related to the fast replication of the virus in vivo.

[0331] Importantly, it has been demonstrated clinically that EnAd can be administered systemically (e.g. by intravenous or intraperitoneal injection or infusion) and then subsequently selectively infect and express proteins within tumour cells. This property of EnAd, which may be shared by Ad11p and other group B adenoviruses in particular those expressing the capsid proteins of Ad11p (such as those described herein), makes it possible to express proteins on the surface of cancer cells without having to directly inject the transgenes into the tumour, which is not feasible for many cancers.

[0332] Whilst EnAd selectively lyses tumour cells, it may be possible to introduce further beneficial properties, for example increasing the therapeutic activity of the virus or reducing side-effects of the virus by arming it with transgenes, such as a transgene which encodes a cell signalling protein or an antibody, or a transgene which encodes an entity which stimulates a cell signalling protein(s).

[0333] Advantageously arming a virus, with DNA encoding certain proteins that can be expressed inside the cancer cell, may enable the body's own defences to be employed to combat tumour cells more effectively, for example by making the cells more visible to the immune system or by delivering a therapeutic gene/protein preferentially to target tumour cells.

[0334] In one embodiment the oncolytic adenovirus of the present disclosure stimulates the patient's immune system to fight the tumor, for example by reducing the cancers ability to suppress immune responses.

[0335] In one embodiment the oncolytic virus has a fibre, hexon and penton proteins from the same serotype, for example Ad11, in particular Ad11p, for example found at positions 30812-31789, 18254-21100 and 13682-15367 of the genomic sequence of the latter wherein the nucleotide positions are relative to Genbank ID 217307399 (accession number: GC689208).

[0336] In one embodiment the adenovirus is enadenotucirev (also known as EnAd and formerly as ColoAd1). Enadenotucirev as employed herein refers the chimeric adenovirus of SEQ ID NO: 21. It is a replication competent oncolytic chimeric adenovirus which has enhanced therapeutic properties compared to wild type adenoviruses (see WO2005/118825). EnAd has a chimeric E2B region, which features DNA from Ad11p and Ad3, and deletions in E3/E4. The structural changes in enadenotucirev result in a genome that is approximately 3.5 kb smaller than Ad11p thereby providing additional "space" for the insertion of transgenes.

[0337] Antibody molecules as employed may comprise a complete antibody molecule having full length heavy and light chains, bispecific antibody format comprising full length antibodies or a fragment of any one of the same including, but are not limited to Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, single domain antibodies (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews --Online 2(3), 209-217). The methods for creating and manufacturing these antibody fragments are well known in the art (see for example Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). Other antibody fragments for use in the present invention include the Fab and Fab' fragments described in International patent applications WO2005/003169, WO2005/003170 and WO2005/003171. Multi-valent antibodies may comprise multiple specificities e.g bispecific or may be monospecific (see for example WO 92/22853, WO05/113605, WO2009/040562 and WO2010/035012).

[0338] Antibody as employed herein, unless the context indicated otherwise refers to a full length antibody.

[0339] Antibody binding fragments refers to a fragment comprising a binding domains which, such as a VH and/or VL which retains specificity for the target antigen to which it binds and for example Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, single domain antibodies (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the same.

Linkers

[0340] Linkers suitable for use in fusion proteins of the present disclosure include:

TABLE-US-00005 TABLE 2 Hinge linker sequences SEQ ID NO: SEQUENCE 26 DKTHTCAA 27 DKTHTCPPCPA 28 DKTHTCPPCPATCPPCPA 29 DKTHTCPPCPATCPPCPATCPPCPA 30 DKTHTCPPCPAGKPTLYNSLVMSDTAGTCY 31 DKTHTCPPCPAGKPTHVNVSVVMAEVDGTCY 32 DKTHTCCVECPPCPA 33 DKTHTCPRCPEPKSCDTPPPCPRCPA 34 DKTHTCPSCPA

TABLE-US-00006 TABLE 3 Flexible linker sequences SEQ ID NO: SEQUENCE 35 SGGGGSE 36 DKTHTS 37 (S)GGGGS 38 (S)GGGGSGGGGS 39 (S)GGGGSGGGGSGGGGS 40 (S)GGGGSGGGGSGGGGSGGGGS 41 (S)GGGGSGGGGSGGGGSGGGGSGGGGS 42 AAAGSG-GASAS 43 AAAGSG-XGGGS-GASAS 44 AAAGSG-XGGGSXGGGS-GASAS 45 AAAGSG-XGGGSXGGGSXGGGS-GASAS 46 AAAGSG-XGGGSXGGGSXGGGSXGGGS-GASAS 47 AAAGSG-XS-GASAS 48 PGGNRGTTTTRRPATTTGSSPGPTQSHY 49 ATTTGSSPGPT 50 ATTTGS -- GS 51 EPSGPISTINSPPSKESHKSP 52 GTVAAPSVFIFPPSD 53 GGGGIAPSMVGGGGS 54 GGGGKVEGAGGGGGS 55 GGGGSMKSHDGGGGS 56 GGGGNLITIVGGGGS 57 GGGGVVPSLPGGGGS 58 GGEKSIPGGGGS 59 RPLSYRPPFPFGFPSVRP 60 YPRSIYIRRRHPSPSLTT 61 TPSHLSHILPSFGLPTFN 62 RPVSPFTFPRLSNSWLPA 63 SPAAHFPRSIPRPGPIRT 64 APGPSAPSHRSLPSRAFG 65 PRNSIHFLHPLLVAPLGA 66 MPSLSGVLQVRYLSPPDL 67 SPQYPSPLTLTLPPHPSL 68 NPSLNPPSYLHRAPSRIS 69 LPWRTSLLPSLPLRRRP 70 PPLFAKGPVGLLSRSFPP 71 VPPAPVVSLRSAHARPPY 72 LRPTPPRVRSYTCCPTP- 73 PNVAHVLPLLTVPWDNLR 74 CNPLLPLCARSPAVRTFP

(S) is optional in sequences 37 to 41,

[0341] Examples of rigid linkers include the peptide sequences GAPAPAAPAPA (SEQ ID NO: 75), PPPP (SEQ ID NO: 76) and PPP.

Other linkers are shown in Table 4:

TABLE-US-00007 SEQ ID NO: SEQUENCE 77 DLCLRDWGCLW 78 DICLPRWGCLW 79 MEDICLPRWGCLWGD 80 QRLMEDICLPRWGCLWEDDE 81 QGLIGDICLPRWGCLWGRSV 82 QGLIGDICLPRWGCLWGRSVK 83 EDICLPRWGCLWEDD 84 RLMEDICLPRWGCLWEDD 85 MEDICLPRWGCLWEDD 86 MEDICLPRWGCLWED 87 RLMEDICLARWGCLWEDD 88 EVRSFCTRWPAEKSCKPLRG 89 RAPESFVCYWETICFERSEQ 90 EMCYFPGICWM

Definitions Relevant to Formula (I) and (Ia)

[0342] A bond refers to a covalent bond connecting the one DNA sequence to another DNA sequence, for example connecting one section of the virus genome to another. Thus when a variable in formula (I) and (Ia) herein represents a bond the feature or element represented by the bond is absent i.e. deleted.

[0343] As the structure of adenoviruses is, in general, similar the elements below are discussed in terms of the structural elements and the commonly used nomenclature referring thereto, which are known to the skilled person. When an element is referred to herein then we refer to the DNA sequence encoding the element or a DNA sequence encoding the same structural protein of the element in an adenovirus. The latter is relevant because of the redundancy of the DNA code. The viruses' preference for codon usage may need to be considered for optimised results.

[0344] Any structural element from an adenovirus employed in the viruses of the present disclosure may comprise or consist of the natural sequence or may have similarity over the given length of at least 95%, such as 96%, 97%, 98%, 99% or 100%. The original sequence may be modified to omit 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the genetic material. The skilled person is aware that when making changes the reading frames of the virus must be not disrupted such that the expression of structural proteins is disrupted.

[0345] In one embodiment the given element is a full-length sequence i.e. the full-length gene. Full length gene as employed herein refers to at least the entirety of the coding sequence of a gene, but may include any associated non-coding regions, especially if they are relevant to the function of the gene.

[0346] In one embodiment the given element is less than a full-length and retains the same or corresponding function as the full-length sequence.

[0347] In one embodiment for a given element which is optional in the constructs of the present disclosure, the DNA sequence may be less than a full-length and have no functionality, for example the E3 region may be totally or partly deleted. However, it may be useful to delete essentially all the E3 region as this optimises the space available for inserting transgenes.

[0348] The structural genes encoding structural or functional proteins of the adenovirus are generally linked by non-coding regions of DNA. Thus there is some flexibility about where to "cut" the genomic sequence of the structural element of interest (especially non-coding regions thereof) for the purpose of inserting a transgene into the viruses of the present disclosure. Thus for the purposes of the present specification, the element will be considered a structural element of reference to the extent that it is fit for purpose and does not encode extraneous material. Thus, if appropriate the gene will be associated with suitable non-coding regions, for example as found in the natural structure of the virus.

[0349] Thus in one embodiment an insert, such as DNA encoding a restriction site and/or transgene, is inserted into a non-coding region of genomic virus DNA, such as an intron or intergenic sequence. Having said this some non-coding regions of adenovirus may have a function, for example in alternative splicing, transcription regulation or translation regulation, and this may need to be taken into consideration.

[0350] The sites identified herein, that are associated with the L5 region, are suitable for accommodating a variety of DNA sequences encoding complex entities such as RNAi, cytokines, single chain or multimeric proteins, such as antibodies.

[0351] Gene as employed herein refers to coding and any non-coding sequences associated therewith, for example introns and associated exons. In one embodiment a gene comprises or consists of only essential structural components, for example coding region.

[0352] Below follows a discussion relating to specific structural elements of adenoviruses.

[0353] The Inverted Terminal Repeat (ITR) sequences are common to all known adenoviruses (so named because of their symmetry) and are the viral chromosome origins of replication. Another property of these sequences is their ability to form a hairpin.

[0354] The 5'ITR as employed herein refers to part or all of an ITR from the 5' end of an adenovirus, which retains the function of the ITR when incorporated into an adenovirus in an appropriate location. In one embodiment the 5'ITR comprises or consists of the sequence from about 1 bp to 138 bp of SEQ ID NO: 21 or a sequence 90, 95, 96, 97, 98 or 99% identical thereto along the whole length, in particular the sequence consisting of from about 1 bp to 138 bp of SEQ ID NO: 21.

[0355] The 3'ITR as employed herein refers to part or all of an ITR from 3' end of an adenovirus which retains the function of the ITR when incorporated into an adenovirus in an appropriate location. In one embodiment the 3'ITR comprises or consists of the sequence from about 32189 bp to 32326 bp of SEQ ID NO: 21 or a sequence 90, 95, 96, 97, 98 or 99% identical thereto along the whole length, in particular the sequence consisting of from about 32189 bp to 32326 bp of SEQ ID NO: 21.

[0356] B1 as employed herein refers to the DNA sequence encoding: part or all of an E1A from an adenovirus, part or all of the E1B region of an adenovirus, and independently part or all of E1A and E1B region of an adenovirus.

[0357] When B1 is a bond then E1A and E1B sequences will be omitted from the virus. In one embodiment B1 is a bond and thus the virus is a vector.

[0358] In one embodiment B1 further comprises a transgene. It is known in the art that the E1 region can accommodate a transgene which may be inserted in a disruptive way into the E1 region (i.e. in the "middle" of the sequence) or part or all of the E1 region may be deleted to provide more room to accommodate genetic material.

[0359] E1A as employed herein refers to the DNA sequence encoding part or all of an adenovirus E1A region. The latter here is referring to the polypeptide/protein E1A. It may be mutated such that the protein encoded by the E1A gene has conservative or non-conservative amino acid changes (e.g. 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions over the whole length) such that it has: the same function as wild-type (i.e. the corresponding non-mutated protein); increased function in comparison to wild-type protein; decreased function, such as no function in comparison to wild-type protein; or has a new function in comparison to wild-type protein or a combination of the same as appropriate.

[0360] E1B as employed herein refers to the DNA sequence encoding part or all of an adenovirus E1B region (i.e. polypeptide or protein), it may be mutated such that the protein encoded by the E1B gene/region has conservative or non-conservative amino acid changes (e.g. 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions over the whole length) such that it has: the same function as wild-type (i.e. the corresponding non-mutated protein); increased function in comparison to wild-type protein; decreased function, such as no function in comparison to wild-type protein; or has a new function in comparison to wild-type protein or a combination of the same as appropriate.

[0361] Thus B1 can be modified or unmodified relative to a wild-type E1 region, such as a wild-type E1A and/or E1B. The skilled person can easily identify whether E1A and/or E1B are present or (part) deleted or mutated.

[0362] Wild-type as employed herein refers to a known adenovirus or a sequence from a known adenovirus. A known adenovirus is one that has been identified and named, regardless of whether the sequence information is available.

[0363] In one embodiment B1 has the sequence from 139 bp to 3932 bp of SEQ ID NO: 21.

[0364] B.sub.A as employed herein refers to the DNA sequence encoding the E2B-L1-L2-L3-E2A-L4 regions including any non-coding sequences, as appropriate (in particular corresponding to the natural sequence from an adenovirus). Generally this sequence will not comprise a transgene. In one embodiment the sequence is substantially similar or identical to a contiguous sequence from a known adenovirus, for example a serotype shown in Table 1, in particular a group B virus, for example Ad3, Ad7, Ad11, Ad14, Ad16, Ad21, Ad34, Ad35, Ad51 or a combination thereof, such as Ad3, Ad11 or a combination thereof.

[0365] In one embodiment is E2B-L1-L2-L3-E2A-L4 refers to comprising these elements and other structural elements associated with the region, for example B.sub.A will generally include the sequence encoding the protein IV2a, for example as follows: IV2A IV2a-E2B-L1-L2-L3-E2A-L4.

[0366] In one embodiment the E2B region is chimeric. That is, comprises DNA sequences from two or more different adenoviral serotypes, for example from Ad3 and Ad11, such as Ad11p. In one embodiment the E2B region has the sequence from 5068 bp to 10355 bp of SEQ ID NO: 21 or a sequence 95%, 96%, 97%, 98% or 99% identical thereto over the whole length.

[0367] In one embodiment the E2B in component B.sub.A comprises the sequences shown in SEQ ID NO: 22 (which corresponds to SEQ ID NO: 3 disclosed in WO2005/118825). In one embodiment B.sub.A has the sequence from 3933 bp to 27184 bp of SEQ ID NO: 21.

[0368] E3 as employed herein refers to the DNA sequence encoding part or all of an adenovirus E3 region (i.e. protein/polypeptide), it may be mutated such that the protein encoded by the E3 gene has conservative or non-conservative amino acid changes (e.g. 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions over the whole length), such that it has the same function as wild-type (the corresponding unmutated protein); increased function in comparison to wild-type protein; decreased function, such as no function in comparison to wild-type protein or has a new function in comparison to wild-type protein or a combination of the same, as appropriate.

[0369] In one embodiment the E3 region is form an adenovirus serotype given in Table 1 or a combination thereof, in particular a group B serotype, for example Ad3, Ad7, Ad11 (in particular Ad11p), Ad14, Ad16, Ad21, Ad34, Ad35, Ad51 or a combination thereof, such as Ad3, Ad11 (in particular Ad11p) or a combination thereof. In one embodiment the E3 region has a sequence shown in SEQ ID NO: 23.

[0370] In one embodiment the E3 region is partially deleted, for example is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% deleted.

[0371] In one embodiment B.sub.2 is a bond, wherein the DNA encoding the E3 region is absent.

[0372] In one embodiment the DNA encoding the E3 region can be replaced or interrupted by a transgene. As employed herein "E3 region replaced by a transgene as employed herein includes part or all of the E3 region is replaced with a transgene.

[0373] In one embodiment the B.sub.2 region comprises the sequence from 27185 bp to 28165 bp of SEQ ID NO: 24.

[0374] In one embodiment B.sub.2 consists of the sequence from 27185 bp to 28165 bp of SEQ ID NO: 24.

[0375] B.sub.X as employed herein refers to the DNA sequence in the vicinity of the 5' end of the L5 gene in B.sub.B. In the vicinity of or proximal to the 5' end of the L5 gene as employed herein refers to: adjacent (contiguous) to the 5' end of the L5 gene or a non-coding region inherently associated herewith i.e. abutting or contiguous to the 5' prime end of the L5 gene or a non-coding region inherently associated therewith. Alternatively, in the vicinity of or proximal to may refer to being close the L5 gene, such that there are no coding sequences between the BX region and the 5' end of L5 gene.

[0376] Thus in one embodiment B.sub.X is joined directly to a base of L5 which represents, for example the start of a coding sequence of the L5 gene.

[0377] Thus in one embodiment B.sub.X is joined directly to a base of L5 which represents, for example the start of a non-coding sequence, or joined directly to a non-coding region naturally associated with L5. A non-coding region naturally associated L5 as employed herein refers to part of all of a non-coding regions which is part of the L5 gene or contiguous therewith but not part of another gene.

[0378] In one embodiment B.sub.X comprises the sequence of SEQ ID NO: 24. This sequence is an artificial non-coding sequence wherein a DNA sequence, for example comprising a transgene (or transgene cassette), a restriction site or a combination thereof may be inserted therein. This sequence is advantageous because it acts as a buffer in that allows some flexibility on the exact location of the transgene whilst minimising the disruptive effects on virus stability and viability.

[0379] The insert(s) can occur anywhere within SEQ ID NO: 24 from the 5' end, the 3' end or at any point between bp 1 to 201, for example between base pairs 1/2, 2/3, 3/4, 4/5, 5/6, 6/7, 7/8, 8/9, 9/10, 10/11, 11/12, 12/13, 13/14, 14/15, 15/16, 16/17, 17/18, 18/19, 19/20, 20/21, 21/22, 22/23, 23/24, 24/25, 25/26, 26/27, 27/28, 28/29, 29/30, 30/31, 31/32, 32/33, 33/34, 34/35, 35/36, 36/37, 37/38, 38/39, 39/40, 40/41, 41/42, 42/43, 43/44, 44/45, 45/46, 46/47, 47/48, 48/49, 49/50, 50/51, 51/52, 52/53, 53/54, 54/55, 55/56, 56/57, 57/58, 58/59, 59/60, 60/61, 61/62, 62/63, 63/64, 64/65, 65/66, 66/67, 67/68, 68/69, 69/70, 70/71, 71/72, 72/73, 73/74, 74/75, 75/76, 76/77, 77/78, 78/79, 79/80, 80/81, 81/82, 82/83, 83/84, 84/85, 85/86, 86/87, 87/88, 88/89, 89/90, 90/91, 91/92, 92/93, 93/94, 94/95, 95/96, 96/97, 97/98, 98/99, 99/100, 100/101, 101/102, 102/103, 103/104, 104/105, 105/106, 106/107, 107/108, 108/109, 109/110, 110/111, 111/112, 112/113, 113/114, 114/115, 115/116, 116/117, 117/118, 118/119, 119/120, 120/121, 121/122, 122/123, 123/124, 124/125, 125/126, 126/127, 127/128, 128/129, 129/130, 130/131, 131/132, 132/133, 133/134, 134/135, 135/136, 136/137, 137/138, 138/139, 139/140, 140/141, 141/142, 142/143, 143/144, 144/145, 145/146, 146/147, 147/148, 148/149, 150/151, 151/152, 152/153, 153/154, 154/155, 155/156, 156/157, 157/158, 158/159, 159/160, 160/161, 161/162, 162/163, 163/164, 164/165, 165/166, 166/167, 167/168, 168/169, 169/170, 170/171, 171/172, 172/173, 173/174, 174/175, 175/176, 176/177, 177/178, 178/179, 179/180, 180/181, 181/182, 182/183, 183/184, 184/185, 185/186, 186/187, 187/188, 189/190, 190/191, 191/192, 192/193, 193/194, 194/195, 195/196, 196/197, 197/198, 198/199, 199/200 or 200/201.

[0380] In one embodiment B.sub.X comprises SEQ ID NO: 24 with a DNA sequence inserted between bp 27 and bp 28 or a place corresponding to between positions 28192 bp and 28193 bp of SEQ ID NO: 24.

[0381] In one embodiment B.sub.X has the sequence from 28166 bp to 28366 bp of SEQ ID NO: 21. In one embodiment B.sub.X is a bond.

[0382] B.sub.B as employed herein refers to the DNA sequence encoding the L5 region. As employed herein the L5 region refers to the DNA sequence containing the gene encoding the fibre polypeptide/protein, as appropriate in the context. The fibre gene/region encodes the fibre protein which is a major capsid component of adenoviruses. The fibre functions in receptor recognition and contributes to the adenovirus' ability to selectively bind and infect cells.

[0383] In viruses of the present disclosure the fibre can be from any adenovirus serotype and adenoviruses which are chimeric as result of changing the fibre for one of a different serotype are also envisaged with the present disclosure. In one embodiment the fibre is from a group B virus, in particular Ad11, such as Ad11p.

[0384] In one embodiment B.sub.B has the sequence from 28367 bp to 29344 bp of SEQ ID NO: 21.

[0385] DNA sequence in relation to B.sub.Y as employed herein refers to the DNA sequence in the vicinity of the 3' end of the L5 gene of B.sub.B. In the vicinity of or proximal to the 3' end of the L5 gene as employed herein refers to: adjacent (contiguous) to the 3' end of the L5 gene or a non-coding region inherently associated therewith i.e. abutting or contiguous to the 3' prime end of the L5 gene or a non-coding region inherently associated therewith (i.e. all or part of an non-coding sequence endogenous to L5). Alternatively, in the vicinity of or proximal to may refer to being close the L5 gene, such that there are no coding sequences between the B.sub.Y region and the 3' end of the L5 gene.

[0386] Thus in one embodiment B.sub.Y is joined directly to a base of L5 which represents the "end" of a coding sequence.

[0387] Thus in one embodiment B.sub.Y is joined directly to a base of L5 which represents the "end" of a non-coding sequence, or joined directly to a non-coding region naturally associated with L5.

[0388] Inherently and naturally are used interchangeably herein. In one embodiment By comprises the sequence of SEQ ID NO: 25. This sequence is a non-coding sequence wherein a DNA sequence, for example comprising a transgene (or transgene cassette), a restriction site or a combination thereof may be inserted. This sequence is advantageous because it acts a buffer in that allows some flexibility on the exact location of the transgene whilst minimising the disruptive effects on virus stability and viability.

[0389] The insert(s) can occur anywhere within SEQ ID NO: 22 from the 5' end, the 3' end or at any point between bp 1 to 35, for example between base pairs 1/2, 2/3, 3/4, 4/5, 5/6, 6/7, 7/8, 8/9, 9/10, 10/11, 11/12, 12/13, 13/14, 14/15, 15/16, 16/17, 17/18, 18/19, 19/20, 20/21, 21/22, 22/23, 23/24, 24/25, 25/26, 26/27, 27/28, 28/29, 29/30, 30/31, 31/32, 32/33, 33/34, or 34/35.

[0390] In one embodiment B.sub.Y comprises SEQ ID NO: 25 with a DNA sequence inserted between positions bp 12 and 13 or a place corresponding to 29356 bp and 29357 bp in SEQ ID NO: 21. In one embodiment the insert is a restriction site insert. In one embodiment the restriction site insert comprises one or two restriction sites. In one embodiment the restriction site is a 19 bp restriction site insert comprising 2 restriction sites. In one embodiment the restriction site insert is a 9 bp restriction site insert comprising 1 restriction site. In one embodiment the restriction site insert comprises one or two restriction sites and at least one transgene, for example one or two or three transgenes, such as one or two transgenes. In one embodiment the restriction site is a 19 bp restriction site insert comprising 2 restriction sites and at least one transgene, for example one or two transgenes. In one embodiment the restriction site insert is a 9 bp restriction site insert comprising 1 restriction site and at least one transgene, for example one or two transgenes. In one embodiment two restriction sites sandwich one or more, such as two transgenes (for example in a transgene cassette). In one embodiment when B.sub.Y comprises two restrictions sites the said restriction sites are different from each other. In one embodiment said one or more restrictions sites in B.sub.Y are non-naturally occurring (such as unique) in the particular adenovirus genome into which they have been inserted. In one embodiment said one or more restrictions sites in B.sub.Y are different to other restrictions sites located elsewhere in the adenovirus genome, for example different to naturally occurring restrictions sites or restriction sites introduced into other parts of the genome, such as B.sub.X. Thus in one embodiment the restriction site or sites allow the DNA in the section to be cut specifically.

[0391] In one embodiment B.sub.Y has the sequence from 29345 bp to 29379 bp of SEQ ID NO: 21. In one embodiment B.sub.Y is a bond.

[0392] In one embodiment the insert is after bp 12 in SEQ ID NO: 25.

[0393] In one embodiment the insert is at about position 29356 bp of SEQ ID NO: 21.

[0394] In one embodiment the insert is a transgene cassette comprising one or more transgenes, for example 1, 2 or 3, such as 1 or 2.

[0395] E4 as employed herein refers to the DNA sequence encoding part or all of an adenovirus E4 region (i.e. polypeptide/protein region), which may be mutated such that the protein encoded by the E4 gene has conservative or non-conservative amino acid changes (e.g. 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions), and has the same function as wild-type (the corresponding non-mutated protein); increased function in comparison to wild-type protein; decreased function, such as no function in comparison to wild-type protein or has a new function in comparison to wild-type protein or a combination of the same as appropriate.

[0396] In one embodiment the E4 region is partially deleted, for example is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5% deleted. In one embodiment the E4 region has the sequence from 32188 bp to 29380 bp of SEQ ID NO: 21.

[0397] In one embodiment E4 is present except for the E4orf4 region which is deleted.

[0398] In one embodiment B.sub.3 is a bond, i.e. wherein E4 is absent.

[0399] In one embodiment B.sub.3 has the sequence consisting of from 32188 bp to 29380 bp of SEQ ID NO: 21.

[0400] As employed herein number ranges are inclusive of the end points.

[0401] The skilled person will appreciate that the elements in the formulas herein, such as formula (I), (Ia) are contiguous and may embody non-coding DNA sequences as well as the genes and coding DNA sequences (structural features) mentioned herein. In one or more embodiments the formulas of the present disclosure are attempting to describe a naturally occurring sequence in the adenovirus genome. In this context it will be clear to the skilled person that the formula is referring to the major elements characterising the relevant section of genome and is not intended to be an exhaustive description of the genomic stretch of DNA.

[0402] E1A, E1B, E3 and E4 as employed herein each independently refer to the wild-type and equivalents thereof, mutated or partially deleted forms of each region as described herein, in particular a wild-type sequence from a known adenovirus.

[0403] "Insert" as employed herein refers to a DNA sequence that is incorporated either at the 5' end, the 3' end or within a given DNA sequence reference segment such that it interrupts the reference sequence. A reference sequence employed as a reference point relative to which the insert is located. In the context of the present disclosure inserts generally occur within either SEQ ID NO: 24 or SEQ ID NO: 25. An insert can be either a restriction site insert, a transgene cassette or both. When the sequence is interrupted the virus will still comprise the original sequence, but generally it will be as two fragments sandwiching the insert.

[0404] In one embodiment the transgene or transgene cassette does not comprise a non-biased inserting transposon, such as a TN7 transposon or part thereof. Tn7 transposon as employed herein refers to a non-biased insertion transposon as described in WO2008/080003.

[0405] In one embodiment the transgene or transgene cassette further comprises a regulatory element or sequence.

Other Regulatory Sequences

[0406] "Regulator of gene expression" (or regulator/regulatory element) as employed herein refers to a genetic element, such as a promoter, enhancer or a splice acceptor sequence that plays a role in gene expression, typically by initiating or enhancing transcription or translation.

[0407] "Splice acceptor sequence", "splice acceptor" or "splice site" as employed herein refers to a regulatory sequence determining when an mRNA molecule will be recognised by small nuclear ribonucleoproteins of the spliceosome complex. Once assembled the spliceosome catalyses splicing between the splice acceptor site of the mRNA molecule to an upstream splice donor site producing a mature mRNA molecule that can be translated to produce a single polypeptide or protein.

[0408] Different sized splice acceptor sequences may be employed in the present invention and these can be described as short splice acceptor (small), splice acceptor (medium) and branched splice acceptor (large).

[0409] SSA as employed herein refers to a short splice acceptor, typically comprising just the splice site, for example 4 bp. SA as employed herein refers to a splice acceptor, typically comprising the short splice acceptor and the polypyrimidine tract, for example 16 bp. bSA as employed herein refers to a branched splice acceptor, typically comprising the short splice acceptor, polypyrimidine tract and the branch point, for example 26 bp.

[0410] In one embodiment the splice acceptor employed in the constructs of the disclosure are CAGG or SEQ ID NO: 3 or 4. In one embodiment the SSA has the nucleotide sequence of SEQ ID NO: CAGG. In one embodiment the SA has the nucleotide sequence of SEQ ID NO: 23. In one embodiment the bSA has the nucleotide sequence of cagg. In one embodiment the splice acceptor sequence is independently selected from the group comprising: tgctaatctt cctttctctc ttcagg (SEQ ID NO: 4), tttctctctt cagg (SEQ ID NO: 3), and cagg.

[0411] In one embodiment the splice site is immediately proceeded (i.e. followed in a 5' to 3' direction) by a consensus Kozak sequence comprising CCACC. In one embodiment the splice site and the Kozak sequence are interspersed (separated) by up to 100 or less bp. In one embodiment the Kozak sequence has the nucleotide sequence of CCACC.

[0412] Typically, when under the control of an endogenous or exogenous promoter (such as an endogenous promoter), the coding sequence will be immediately preceded by a Kozak sequence. The start of the coding region is indicated by the initiation codon (AUG), for example is in the context of the sequence (gcc)gccRccAUGg [SEQ ID NO: 105] the start of the start of the coding sequences is indicated by the bases in bold. A lower case letter denotes common bases at this position (which can nevertheless vary) and upper case letters indicate highly-conserved bases, i.e. the `AUGG` sequence is constant or rarely, if ever, changes; `R` indicates that a purine (adenine or guanine) is usually observed at this position and the sequence in brackets (gcc) is of uncertain significance. Thus in one embodiment the initiation codon AUG is incorporated into a Kozak sequence.

[0413] Internal Ribosome Entry DNA Sequence as employed herein refers to a DNA sequence encoding an Internal Ribosome Entry Sequence (IRES). IRES as employed herein means a nucleotide sequence that allows for initiation of translation a messenger RNA (mRNA) sequence, including initiation starting within an mRNA sequence. This is particularly useful when the cassette encodes polycistronic mRNA. Using an IRES results in a polycistronic mRNA that is translated into multiple individual proteins or peptides. In one embodiment the Internal Ribosome Entry DNA sequence has the nucleotide sequence of SEQ ID NO: 6. In one embodiment a particular IRES is only used once in the genome. This may have benefits with respect to stability of the genome.

[0414] "High self-cleavage efficiency 2A peptide" or "2A peptide" as employed herein refers to a peptide which is efficiently cleaved following translation. Suitable 2A peptides include P2A, F2A, E2A and T2A. The present inventors have noted that once a specific DNA sequence encoding a given 2A peptide is used once, the same specific DNA sequence may not be used a second time. However, redundancy in the DNA code may be utilised to generate a DNA sequence that is translated into the same 2A peptide. Using 2A peptides is particularly useful when the cassette encodes polycistronic mRNA. Using 2A peptides results in a single polypeptide chain being translated which is modified post-translation to generate multiple individual proteins or peptides.

[0415] In one embodiment the encoded P2A peptide employed has the amino acid sequence of SEQ ID NO: 7. In one embodiment the encoded F2A peptide employed has the amino acid sequence of SEQ ID NO: 8. In one embodiment the encoded E2A peptide employed has the amino acid sequence of SEQ ID NO: 9. In one embodiment the encoded T2A peptide employed has the amino acid sequence of SEQ ID NO: 10.

[0416] In one embodiment an mRNA or each mRNA encoded by transgene is/are comprise a polyadenylation signal sequence, such as typically at the end of an mRNA sequence, for example as shown in SEQ ID NO: 5. Thus in one embodiment the transgene or the transgene cassette comprises at least one sequence encoding a polyadenylation signal sequence.

[0417] "PolyA", "Polyadenylation signal" or "polyadenylation sequence" as employed herein means a DNA sequence, usually containing an AATAAA site, that once transcribed can be recognised by a multiprotein complex that cleaves and polyadenylates the nascent mRNA molecule.

[0418] In one embodiment the polyadenylation sequence has the nucleotide sequence of SEQ ID NO: 5.

[0419] In one embodiment the construct does not include a polyadenylation sequence. In one embodiment the regulator of gene expression is a splice acceptor sequence.

[0420] In one embodiment the sequence encoding a protein/polypeptide/peptide, such as an antibody or antibody binding fragment further comprises a polyadenylation signal.

[0421] In one embodiment there is provided a virus or construct with a sequence disclosed herein, for example a virus selected NG-330 (SEQ ID NO: 16); NG-334 (SEQ ID NO: 17); NG-345 (SEQ ID NO: 18); NG-346 (SEQ ID NO: 19); NG-347 (SEQ ID NO: 20) and NG-348 (SEQ ID NO: 96).

In one embodiment the virus is NG-347 (SEQ ID NO: 20) or NG-348 (SEQ ID NO: 96).

Formulations

[0422] The present disclosure relates also extends to a pharmaceutical formulation of a virus as described herein.

[0423] In one embodiment there is provided a liquid parenteral formulation, for example for infusion or injection, of a replication capable oncolytic according to the present disclosure wherein the formulation provides a dose in the range of 1.times.10.sup.10 to 1.times.10.sup.14 viral particles per volume of dose.

[0424] Parenteral formulation means a formulation designed not to be delivered through the GI tract. Typical parenteral delivery routes include injection, implantation or infusion. In one embodiment the formulation is provided in a form for bolus delivery.

[0425] In one embodiment the parenteral formulation is in the form of an injection. Injection includes intravenous, subcutaneous, intra-tumoral or intramuscular injection. Injection as employed herein means the insertion of liquid into the body via a syringe. In one embodiment the method of the present disclosure does not involve intra-tumoral injection.

[0426] In one embodiment the parenteral formulation is in the form of an infusion.

[0427] Infusion as employed herein means the administration of fluids at a slower rate by drip, infusion pump, syringe driver or equivalent device. In one embodiment the infusion is administered over a period in the range of 1.5 minutes to 120 minutes, such as about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 65, 80, 85, 90, 95, 100, 105, 110 or 115 minutes.

[0428] In one embodiment one dose of the formulation less than 100 mls, for example 30 mls, such as administered by a syringe driver.

[0429] In one embodiment the injection is administered as a slow injection, for example over a period of 1.5 to 30 minutes.

[0430] In one embodiment the formulation is for intravenous (i.v.) administration. This route is particularly effective for delivery of oncolytic virus because it allows rapid access to the majority of the organs and tissue and is particular useful for the treatment of metastases, for example established metastases especially those located in highly vascularised regions such as the liver and lungs.

[0431] Therapeutic formulations typically will be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other parenteral formulation suitable for administration to a human and may be formulated as a pre-filled device such as a syringe or vial, particular as a single dose.

[0432] The formulation will generally comprise a pharmaceutically acceptable diluent or carrier, for example a non-toxic, isotonic carrier that is compatible with the virus, and in which the virus is stable for the requisite period of time.

[0433] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a dispersant or surfactant such as lecithin or a non-ionic surfactant such as polysorbate 80 or 40. In dispersions the maintenance of the required particle size may be assisted by the presence of a surfactant. Examples of isotonic agents include sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.

[0434] In one embodiment parenteral formulations employed may comprise one or more of the following a buffer, for example 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, a phosphate buffer and/or a Tris buffer, a sugar for example dextrose, mannose, sucrose or similar, a salt such as sodium chloride, magnesium chloride or potassium chloride, a detergent such as a non-ionic surfactant such as brij, PS-80, PS-40 or similar. The formulation may also comprise a preservative such as EDTA or ethanol or a combination of EDTA and ethanol, which are thought to prevent one or more pathways of possible degradation.

[0435] In one embodiment the formulation will comprise purified oncolytic virus according to the present disclosure, for example 1.times.10.sup.10 to 1.times.10.sup.14 viral particles per dose, such as 1.times.10.sup.10 to 1.times.10.sup.12 viral particles per dose. In one embodiment the concentration of virus in the formulation is in the range 2.times.10.sup.8 to 2.times.10.sup.14 vp/ml, such as 2.times.10.sup.12 vp/ml.

[0436] In one embodiment the parenteral formulation comprises glycerol.

[0437] In one embodiment the formulation comprises oncolytic adenovirus as described herein, HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), glycerol and buffer.

[0438] In one embodiment the parenteral formulation consists of virus of the disclosure, HEPES for example 5 mM, glycerol for example 5-20% (v/v), hydrochloric acid, for example to adjust the pH into the range 7-8 and water for injection.

[0439] In one embodiment 0.7 mL of virus of the disclosure at a concentration of 2.times.10.sup.12 vp/mL is formulated in 5 mM HEPES, 20% glycerol with a final pH of 7.8.

[0440] A thorough discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Publishing Company, N.J. 1991).

[0441] In one embodiment the formulation is provided as a formulation for topical administrations including inhalation.

[0442] Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases. Inhalable powders according to the disclosure will generally contain a virus as described herein with a physiologically acceptable excipient.

[0443] These inhalable powders may include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextranes), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these with one another. Mono- or disaccharides are suitably used, such as lactose or glucose, particularly but not exclusively in the form of their hydrates.

[0444] Particles for deposition in the lung require a particle size less than 10 microns, such as 1-9 microns for example from 0.1 to 5 m, in particular from 1 to 5 m. The size of the particle carrying the virus is of primary importance and thus in one embodiment the virus according to the present disclosure may be adsorbed or absorbed onto a particle, such as a lactose particle of the given size.

[0445] The propellant gases which can be used to prepare the inhalable aerosols are known in the art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases may be used on their own or in mixtures thereof.

[0446] Particularly suitable propellant gases are halogenated alkane derivatives selected from among TG 11, TG 12, TG 134a and TG227. Of the abovementioned halogenated hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are particularly suitable.

[0447] The propellant gas-containing inhalable aerosols may also contain other ingredients, such as co-solvents, stabilisers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.

[0448] The propellant gas-containing inhalable aerosols according to the invention may contain up to 5% by weight of active substance. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1% by weight of active ingredient.

[0449] Alternatively, topical administrations to the lung may also be by administration of a liquid solution or suspension formulation, for example employing a device such as a nebulizer, for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus.RTM. nebulizer connected to a Pari Master.RTM. compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.).

[0450] The virus of the invention can be delivered dispersed in a solvent, e.g. in the form of a solution or a suspension, for example as already described above for parenteral formulations. It can be suspended in an appropriate physiological solution, e.g., saline or other pharmacologically acceptable solvent or a buffered solution. Buffered solutions known in the art may contain 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water so as to achieve a pH of about 4.0 to 5.0.

[0451] The therapeutic suspensions or solution formulations can also contain one or more excipients. Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Solutions or suspensions can be encapsulated in liposomes or biodegradable microspheres. The formulation will generally be provided in a substantially sterile form employing sterile manufacture processes.

[0452] This may include production and sterilization by filtration of the buffered solvent/solution used for the formulation, aseptic suspension of the antibody in the sterile buffered solvent solution and dispensing of the formulation into sterile receptacles by methods familiar to those of ordinary skill in the art.

[0453] Nebulisable formulation according to the present disclosure may be provided, for example, as single dose units (e.g., sealed plastic containers or vials) packed in foil envelopes. Each vial contains a unit dose in a volume, e.g., 2 mL, of solvent/solution buffer.

[0454] The present disclosure also extends to liquid solutions or suspensions delivered intra-nasally, for example employing a device as disclosed in WO2009/068877 and US2004/0153033 both incorporated herein by reference.

Treatment

[0455] In a further aspect the present disclosure extends to a virus or a formulation thereof as described herein for use in treatment, in particular for the treatment of cancer.

[0456] In one embodiment the method of treatment is for use in the treatment of a tumour.

[0457] Tumour as employed herein is intended to refer to an abnormal mass of tissue that results from excessive cell division that is uncontrolled and progressive, also called a neoplasm. Tumours may be either benign (not cancerous) or malignant. Tumour encompasses all forms of cancer and metastases. In one embodiment the tumour is cancerous.

[0458] In one embodiment the tumour is a solid tumour. The solid tumour may be localised or metastasised.

[0459] In one embodiment the tumour is of epithelial origin.

[0460] In one embodiment the tumour is a malignancy, such as colorectal cancer, hepatoma, prostate cancer, pancreatic cancer, breast cancer, ovarian cancer, thyroid cancer, renal cancer, bladder cancer, head and neck cancer or lung cancer.

[0461] In one embodiment the tumour is a colorectal malignancy.

[0462] Malignancy as employed herein refers to cancerous cells.

[0463] In one embodiment the oncolytic adenovirus is employed in the treatment or prevention of metastasis.

[0464] In one embodiment the method or formulation herein is employed in the treatment of drug resistant cancers.

[0465] In one embodiment the virus is administered in combination with the administration of a further cancer treatment or therapy.

[0466] In one embodiment there is provided a virus or formulation according to the present disclosure for use in the manufacture of a medicament for the treatment of cancer, for example a cancer described above.

[0467] In a further aspect there is provide a method of treating cancer comprising administering a therapeutically effective amount of a virus or formulation according to the present disclosure to a patient in need thereof, for example a human patient.

[0468] In one embodiment the oncolytic virus or formulation herein is administered in combination with another therapy.

[0469] "In combination" as employed herein is intended to encompass where the oncolytic virus is administered before, concurrently and/or post cancer treatment or therapy. However, generally the treatment regimens for the combination thera

[0470] Cancer therapy includes surgery, radiation therapy, targeted therapy and/or chemotherapy.

[0471] Cancer treatment as employed herein refers to treatment with a therapeutic compound or biological agent, for example an antibody intended to treat the cancer and/or maintenance therapy thereof.

[0472] In one embodiment the cancer treatment is selected from any other anti-cancer therapy including a chemotherapeutic agent; a targeted anticancer agent, such as an antibody drug conjugate; radiotherapy, radio-isotope therapy or any combination thereof.

[0473] In one embodiment the virus of the present disclosure such as an oncolytic adenovirus may be used as a pre-treatment to the therapy, such as a surgery (neoadjuvant therapy), to shrink the tumour, to treat metastasis and/or prevent metastasis or further metastasis. The oncolytic adenovirus may be used after the therapy, such as a surgery (adjuvant therapy), to treat metastasis and/or prevent metastasis or further metastasis.

[0474] In one embodiment a virus or formulation of the present disclosure is employed in maintenance therapy.

[0475] Concurrently as employed herein is the administration of the additional cancer treatment at the same time or approximately the same time as the oncolytic adenovirus formulation. The treatment may be contained within the same formulation or administered as a separate formulation.

[0476] In one embodiment the virus is administered in combination with the administration of a chemotherapeutic agent.

[0477] Chemotherapeutic agent as employed herein is intended to refer to specific antineoplastic chemical agents or drugs that are selectively destructive to malignant cells and tissues. For example, alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumour agents. Examples of specific chemotherapeutic agents include doxorubicin, 5-fluorouracil (5-FU), paclitaxel, capecitabine, irinotecan, and platins such as cisplatin and oxaliplatin. The dose may be chosen by the practitioner based on the nature of the cancer being treated.

[0478] In one embodiment the therapeutic agent is ganciclovir, which may assist in controlling immune responses and/or tumour vascularisation.

[0479] In one embodiment one or more therapies employed in the method herein are metronomic, that is a continuous or frequent treatment with low doses of anticancer drugs, often given concomitant with other methods of therapy.

[0480] Subgroup B oncolytic adenoviruses, in particular Ad11 and those derived therefrom such as EnAd may be particularly synergistic with chemotherapeutics because they seem to have a mechanism of action that is largely independent of apoptosis, killing cancer cells by a predominantly necrolytic mechanism. Moreover, the immunosuppression that occurs during chemotherapy may allow the oncolytic virus to function with greater efficiency.

[0481] Therapeutic dose as employed herein refers to the amount of virus, such as oncolytic adenovirus that is suitable for achieving the intended therapeutic effect when employed in a suitable treatment regimen, for example ameliorates symptoms or conditions of a disease, in particular without eliciting dose limiting side effects. A dose may be considered a therapeutic dose in the treatment of cancer or metastases when the number of viral particles may be sufficient to result in the following: tumour or metastatic growth is slowed or stopped, or the tumour or metastasis is found to shrink in size, and/or the life span of the patient is extended. Suitable therapeutic doses are generally a balance between therapeutic effect and tolerable toxicity, for example where the side-effect and toxicity are tolerable given the benefit achieved by the therapy.

[0482] In one embodiment there is provided systemically administering multiple doses of a parenteral formulation of an oncolytic adenovirus according to the present disclosure in a single treatment cycle, for example wherein the total dose given in each administration is in the range of 1.times.10.sup.10 to 1.times.10.sup.14 viral particles per dose.

[0483] In one embodiment one or more doses (for example each dose) of virus or composition comprising the same is administered such that the rate of viral particle delivery is in the range of 2.times.10.sup.10 particles per minute to 2.times.10.sup.12 particles per minute.

[0484] In one embodiment a virus or therapeutic construct according to the present disclosure (including a formulation comprising same) is administered weekly, for example one week 1 the dose is administered on day 1, 3, 5, followed by one dose each subsequent week.

[0485] In one embodiment a virus or therapeutic construct according to the present disclosure (including a formulation comprising same) is administered bi-weekly or tri-weekly, for example is administered in week 1 one on days 1, 3 and 5, and on week 2 or 3 is also administered on days 1, 3 and 5 thereof. This dosing regimen may be repeated as many times as appropriate.

[0486] In one embodiment a virus or therapeutic construct according to the present disclosure (including a formulation comprising same) is administered monthly, for example in a treatment cycle or as maintenance therapy.

[0487] In one embodiment the viruses and constructs of the present disclosure are prepared by recombinant techniques. The skilled person will appreciate that the armed adenovirus genome can be manufactured by other technical means, including entirely synthesising the genome or a plasmid comprising part of all of the genome. The skilled person will appreciate that in the event of synthesising the genome the region of insertion may not comprise the restriction site nucleotides as the latter are artefacts following insertion of genes using cloning methods.

[0488] In one embodiment the armed adenovirus genome is entirely synthetically manufactured, for example as per SEQ ID NO: 109, which was employed with transgene cassettes in SEQ ID Nos: 18, 20, 96, 101, 102, 103.

[0489] The disclosure herein further extends to an adenovirus of formula (I) or a sub-formula thereof, obtained or obtainable from inserting a transgene or transgene cassette.

[0490] "Is" as employed herein means comprising.

[0491] In the context of this specification "comprising" is to be interpreted as "including".

[0492] Embodiments of the invention comprising certain features/elements are also intended to extend to alternative embodiments "consisting" or "consisting essentially" of the relevant elements/features.

[0493] Where technically appropriate, embodiments of the invention may be combined. Technical references such as patents and applications are incorporated herein by reference.

[0494] Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.

[0495] Heading herein are employed to divide the document into sections and are not intended to be used to construe the meaning of the disclosure provided herein.

[0496] The present invention is further described by way of illustration only in the following examples.

EXAMPLES

Example 1: Production of EnAd Virus Expressing the T Cell Activating Antigen CD80

[0497] The plasmid pEnAd2.4 was used to generate the plasmid pNG-330 by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO: 11). The pNG-330 cassette contains a 5' short splice acceptor sequence CAGG, human CD80 cDNA sequence and a 3' polyadenylation sequence (SEQ ID NO: 5). A Schematic of the inserted transgene cassette is shown in FIG. 3A. Construction of the plasmid was confirmed by DNA sequencing.

Virus Production and characterisation

[0498] References herein to viruses such as NG-330-00 are simply references to particular batched "00" of the virus NG-330. Similar nomenclature may be used for other viruses.

[0499] The plasmid pNG-330 was linearised by restriction digest with the enzyme AscI to produce the virus genome NG-330 (SEQ ID NO: 16). Digested DNA was purified by phenol/chloroform extraction and precipitated for 16 hrs, -20.degree. C. in 300 .mu.l>95% molecular biology grade ethanol and 10 13M Sodium Acetate. The precipitated DNA was pelleted by centrifuging at 14000 rpm, 5 mins and was washed in 500 .mu.l 70% ethanol, before centrifuging again, 14000 rpm, 5 mins. The clean DNA pellet was air dried, resuspended in 500 .mu.l OptiMEM containing 15 .mu.l lipofectamine transfection reagent and incubated for 30 mins, RT. The transfection mixture was then added drop wise to a T-25 flask containing 293 cells grown to 70% confluency. After incubation of the cells with the transfection mix for 2 hrs at 37.degree. C., 5% CO.sub.2 4 mls of cell media (DMEM high glucose with glutamine supplemented with 2% FBS) was added to the cells and the flasks was incubated 37.degree. C., 5% C02.

[0500] The transfected 293 cells were monitored every 24 hrs and were supplemented with additional media every 48-72 hrs. The production of virus was monitored by observation of a significant cytopathic effect (CPE) in the cell monolayer. Once extensive CPE was observed the virus was harvested from 293 cells by three freeze-thaw cycles. The harvested viruses were used to re-infect 293 cells in order to amplify the virus stocks. Viable virus production during amplification was confirmed by observation of significant CPE in the cell monolayer. Once CPE was observed the virus was harvested from 293 cells by three freeze-thaw cycles. The amplified stock was used for further amplification before the virus was purified by double caesium chloride banding to produce a NG-330 virus stock.

Example 2: Characterisation of NG-330 Virus Activity Compared to EnAd in Carcinoma Cell Lines

[0501] NG-330 or EnAd virus replication (assessed by qPCR), and CD80 membrane expression (assessed by flow cytometry (FIGS. 4 and 5) was compared in the colon carcinoma cell line HT-29 and lung carcinoma cell line A549. NG-330 is a virus derived from EnAd that contains a transgene cassette encoding the human T cell activating antigen, CD80 after the EnAd late gene, L5 (Fibre). A schematic of the inserted cassette is shown in FIG. 3A. Production of NG-330 virus is detailed in Example 1. A549 or HT-29 carcinoma cell lines were seeded in 6 well plates at cell densities of 7.5e5 cells/well for A549 cells or 2.e6 cells/well for HT-29 cells. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with, 100 EnAd or NG-330 virus particles per cell (ppc) or were left uninfected. Assays were carried out 24, 48 or 72 hrs post infection.

Virus Replication Assessed by qPCR

[0502] HT-29 and A549 cells lines either infected for 24, 48 or 72 hrs with 100 ppc EnAd or NG-330 or left uninfected were used for quantification of viral DNA by qPCR. Cell supernatants were collected and clarified by centrifuging for 5 mins, 1200 rpm. DNA was extracted from 10 .mu.l of supernatant using the Sigma Genelute DNA extraction Kit, according to the manufacturer's protocol. A standard curve using EnAd virus particles (2.5e10-2.5e5vp) was also prepared and extracted using the Sigma Genelute Kit. Each extracted sample or standard was analysed by qPCR using an EnAd E3 gene specific primer-probe set.

[0503] Quantification of the number of detected virus genomes per cell demonstrated that NG-330 and EnAd virus replication was comparable in both HT-29 (FIG. 4A) and A549 cell lines (FIG. 4B). No virus genomes could be detected in uninfected cells (data not shown).

CD80 Cell Surface Expression Assessed by Flow Cytometry

[0504] HT-29 and A549 cells lines either infected for 24, 48 or 72 hrs with 100 ppc EnAd or NG-330 or left uninfected were used for analysis of CD80 transgene expression on the cell surface. The tumour cells were removed from the plate surface by treatment with trypsin, centrifuged and then resuspended in 1% BSA/PBS. Samples were then either incubated at 5.degree. C. for 1 hr with buffer, mouse isotype control antibody conjugated to Cy5 or anti-human CD80 antibody conjugated to Cy5 (clone 2D10). All samples were also co-stained with Zombie Aqua live/dead to differentiate viable cells. Samples were washed 3 times with 1% BSA/PBS before analysis by flow cytometry (FACS, Attune) for cell viability and CD80 protein expression on the cell surface. Analysis showed that CD80 could be detected at the cell surface in both A549 (FIG. 5A) or HT-29 (FIG. 5B) cells treated with NG-330 but not those treated with EnAd or left untreated.

Comparison of virus oncolytic potency

[0505] HT-29 colon carcinoma cells were seeded in 96 well plates at a cell density of 2.5e4 cells/well. Plates were incubated for 4 hrs, 37.degree. C., 5% C02, before cells were either infected with EnAd or NG-330 virus particles at an infection density range of 100-0.39 particles per cell (ppc). HT-29 cell viability was assessed using Cell Titre 96 MTS Reagent (Promega: G3581) 72 hrs post infection. Quantification of the % cell survival at each infection density demonstrated that NG-330 oncolytic potency was comparable to EnAd in HT29 cells (FIG. 6).

Example 3: Production of EnAd Viruses Expressing the T Cell Activating Antigen CD80 and the Cytokine IFN.alpha.

[0506] The plasmid pEnAd2.4 was used to generate the plasmid pNG-343 by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO 11) and the human cytokine interferon .alpha. (IFN.alpha., SEQ ID NO: 12). The pNG-343 cassette contains; a 5' short splice acceptor sequence CAGG; human IFN.alpha. cDNA; a high efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); human CD80 cDNA sequence and a 3' polyadenylation sequence (SEQ ID NO: 5). A Schematic of the inserted transgene cassette is shown in FIG. 3B. Construction of the plasmid was confirmed by DNA sequencing.

Virus Production and Characterisation

[0507] The plasmid pNG-343 was linearised by restriction digest with the enzyme AscI to produce the virus genome NG-343 (SEQ ID NO: 17)). The virus NG-343 is amplified and purified according to methods detailed in Example 1.

Example 4: Production of EnAd Viruses Expressing the Extracellular Domain of FMS-Like Tyrosine Kinase-3 Ligand, the Chemokine MIP1.alpha. and the Cytokine IFN.alpha.

[0508] The plasmid pEnAd2.4 is used to generate the plasmid pNG-345 by direct insertion of a cassette encoding a soluble variant of the FMS-like tyrosine kinase-3 ligand (Flt3L, SEQ ID NO: 13), MIP1.alpha. (isoform LD78s, SEQ ID NO: 14) and IFN.alpha. (SEQ ID NO: 12). The pNG-345 cassette contains; a 5' short splice acceptor sequence CAGG; human Flt3L cDNA; a high efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); human MIP1.alpha. cDNA; a high efficiency self-cleavable T2A peptide sequence (SEQ ID NO: 10); human IFN.alpha. cDNA and a 3' polyadenylation sequence (SEQ ID NO: 5). A Schematic of the inserted transgene cassette is shown in FIG. 3D. Construction of the plasmid is confirmed by DNA sequencing.

Virus Production and Characterisation

[0509] The plasmid pNG-345 is linearised by restriction digest with the enzyme AscI to produce the virus genome NG-345 (SEQ ID NO: 18)). The virus NG-345 is amplified and purified according to methods detailed in Example 1.

Example 5: Production of EnAd Viruses Expressing the T Cell Activating Antigen CD80, the Chemokine MIP1.alpha. and Flt3 Ligand

[0510] The plasmid pEnAd2.4 was used to generate the plasmids pNG-346 by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO 11), the human macrophage Inflammatory Protein 1a (MIP1.alpha., SEQ ID NO. 14) and the human Flt3 Ligand (SEQ ID NO: 13). The pNG-346 cassette contains; a 5' short splice acceptor sequence CAGG; human IFN.alpha. cDNA; a high efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); human MIP1.alpha. cDNA (isoform LD78s); a high efficiency self-cleavable T2A peptide sequence (SEQ ID NO: 10); human Flt3 Ligand cDNA sequence and a 3' polyadenylation sequence (SEQ ID NO: 5). A schematic of the inserted transgene cassette is shown in FIG. 3E. Construction of the plasmid is confirmed by DNA sequencing.

Virus Production and Characterisation

[0511] The plasmid pNG-346 is linearised by restriction digest with the enzyme AscI to produce the virus genome NG-346 (SEQ ID NO: 19). The virus NG-346 is amplified and purified according to methods detailed in Example 1

Example 6: Production of EnAd Viruses Expressing the T Cell Activating Antigen CD80, the Chemokine MIP1.alpha. and the Cytokine IFN.alpha.

[0512] The plasmid pEnAd2.4 was used to generate the plasmids pNG-347 by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO: 11), the human macrophage Inflammatory Protein 1a (MIP1.alpha., SEQ ID NO. 14) and the human cytokine interferon .alpha. (IFN.alpha., SEQ ID NO: 12). The pNG-347 cassette contains; a 5' short splice acceptor sequence CAGG; human IFN.alpha. cDNA; a high efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); human MIP1.alpha. cDNA (isoform LD78s); a high efficiency self-cleavable T2A peptide sequence (SEQ ID NO: 10); human CD80 cDNA sequence and a 3' polyadenylation sequence (SEQ ID NO: 5). A Schematic of the inserted transgene cassette is shown in FIG. 3F. Construction of the plasmid is confirmed by DNA sequencing.

Virus Production and Characterisation

[0513] The plasmid pNG-347 is linearised by restriction digest with the enzyme AscI to produce the virus genome NG-347 (SEQ ID NO: 20). The virus NG-347 is amplified and purified according to methods detailed in Example 1.

Example 7: Production of EnAd Viruses Expressing the T Cell Activating Antigen CD80 and a Membrane-Anchored Single Chain Fv Fragment Antibody to the e Chain of the Human CD3 Complex (CD3e)

[0514] The plasmid pEnAd2.4 was used to generate the plasmids pNG-348 by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO: 11) and a membrane-anchored chimeric form of the single chain Fv anti-human CD3e (SEQ ID NO: 15). The pNG-348 cassette contains; a 5' short splice acceptor sequence CAGG; membrane-anchored anti-human CD3e scFv cDNA; a high efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); human CD80 cDNA sequence and a 3' polyadenylation sequence (SEQ ID NO: 5). A Schematic of the inserted transgene cassette is shown in FIG. 3C. Construction of the plasmid is confirmed by DNA sequencing.

Virus Production and Characterisation

[0515] The plasmid pNG-348 is linearised by restriction digest with the enzyme AscI to produce the virus genome NG-348 (SEQ ID NO: 96). The virus NG-348 is amplified and purified according to methods detailed in Example 1.

Example 8: Activity of EnAd Virus, NG-343, Expressing Two Transgenes; the T Cell Activating Antigen CD80 and the Cytokine IFN.alpha.

Characterisation of NG-343 Virus Activity Compared to EnAd in Carcinoma Cell Lines

[0516] NG-343 or EnAd virus replication (assessed by qPCR), CD80 transgene expression (assessed by flow cytometry) or IFN.alpha. transgene expression (assessed by ELISA) was compared in the colon carcinoma cell line, HT-29 or the lung carcinoma cell line, A549. NG-343 is a virus derived from EnAd that contains a transgene cassette encoding the human T cell activating antigen, CD80 as well as the human cytokine Interferon alpha 2b located after the EnAd late gene, L5 (Fibre). A schematic of the inserted cassette is shown in FIG. 3B. Production of NG-343 virus is detailed in Example 3. A549 or HT-29 carcinoma cell lines were seeded in 12 well plates at cell densities of 7.5.times.10.sup.5 cells/well for A549 cells or 1.4.times.10.sup.6 cells/well for HT-29 cells. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with EnAd or NG-343 at 100 virus particles per cell (ppc) or were left uninfected. Assays were carried out 24, 48 or 72 hrs post infection.

Virus Replication Assessed by qPCR

[0517] HT-29 cells infected for 24, 48 or 72 hrs with 100 ppc EnAd or NG-343 or left uninfected were used for quantification of viral DNA by qPCR. Cell supernatants were collected and clarified by centrifuging for 5 mins, 1200 rpm. DNA was extracted from 10.sup.5 vp of supernatant using the Sigma Genelute DNA extraction Kit, according to the manufacturer's protocol. A standard curve using EnAd virus particles (2.5.times.10.sup.10 to 2.5.times.10.sup.5 vp) was also prepared and extracted using the Sigma Genelute Kit. Each extracted sample or standard was analysed by qPCR using an EnAd E3 gene specific primer-probe set.

[0518] Quantification of the number of detected virus genomes per cell demonstrated that NG-343 and EnAd virus replication was comparable at all time points analysed (FIG. 7A). No virus genomes could be detected in uninfected cells (data not shown).

Analysis of IFN.alpha. Expression by ELISA

[0519] Supernatants of HT-29 or A549 cell lines infected for 24, 48 or 72 hrs with 10 ppc of EnAd or NG-343 or left uninfected were analysed for expression of secreted IFN.alpha. by ELISA. Culture supernatants were removed from each well and centrifuged for 5 mins, 1200 rpm to remove cell debris. Supernatants were diluted into 5% BSA/PBS assay buffer (1:2 or 1:50 or 1:100) and ELISA was carried out using the Verikine Human IFN alpha Kit (Pbl assay science) according to the manufacturer's protocol.

[0520] The concentrations of secreted IFN.alpha. were determined by interpolating from the standard curves. IFN.alpha. expression which increased in the cellular supernatants over the course of infection was detected in both HT-29 and A549 cells lines (FIG. 7B)

CD80 Cell Surface Expression Assessed by Flow Cytometry

[0521] A549 cells lines infected for 48 or 72 hrs with 10 ppc EnAd or NG-343 or left uninfected were used for analysis of CD80 transgene expression on the cell surface. At the appropriate time point post-infection A549 cells were removed from the plate surface by treatment with trypsin, centrifuged and then resuspended in 1% BSA/PBS. Samples were then either incubated at 5.degree. C. for 1 hr with buffer, mouse isotype control antibody conjugated to Cy5 or anti-human CD80 antibody conjugated to Cy5 (clone 2D10). All samples were also co-stained with Zombie Aqua live/dead to differentiate viable cells. Samples were washed 3 times with 1% BSA/PBS before analysis by flow cytometry (FACS, Attune) for cell viability and CD80 protein expression on the cell surface. Analysis of CD80 expression vs Live/dead staining showed that at both 48 and 72 hrs post infection CD80 could be detected at the cell surface of NG-343 treated cells but not EnAd or uninfected control (UIC) cells (FIG. 8). Cell viability at 72 hrs post virus treatment was not sufficient to carry out comprehensive CD80 expression analysis, however high levels of CD80 could be detected on both live and dying cells treated with NG-343 at this time point (FIG. 8D, lower panel).

[0522] CD80 protein expression was then compared in HT-29 and A549 cells at 48 hrs post-infection with 100 ppc. Samples were harvested and stained as above before analysis of cell viability and CD80 protein expression on the cell surface. Analysis of CD80 expression at this time point on only cells stained as live cells showed CD80 could be detected on the surface of .about.91% of NG-343 treated HT-29 cells and .about.-98% of NG-343 treated A549 cells but not on EnAd treated controls.

Example 9: Selectivity of NG-343 Virus Activity and Transgene Expression in Carcinoma, Stromal Fibroblast and Epithelial Cell Lines

[0523] To show that the IFN.alpha. and CD80 transgenes encoded in the NG-343 virus are selectively expressed only in cells permissive to NG-343 or EnAd infection, virus replication (assessed by qPCR), IFN.alpha. expression (assessed by ELISA) and CD80 expression (assessed by flow cytometry) were measured in cancer cells (HT-29) known to be permissive to EnAd infection, fibroblast cell lines (WI-38 and MRC-5) previously characterised to be non-permissive and a bronchial epithelial cell line (BE) which shows only limited permissivity to EnAd infection. Briefly, cells were seeded in 12 well plates and infected 18 hrs post-seeding with 100 ppc NG-343 or EnAd virus for WI38, MRC5 or BE cells or 10 ppc NG-343 or EnAd virus for HT-29 cells. Cells were incubated with virus particles for 4 hrs before the infection media was removed from the cells and replaced with fresh culture media. At 1 hr or 72 hrs post the 4 hr infection period, cell supernatants were harvested for qPCR or ELISA analysis and the cells were treated with trypsin to remove them from the plates for analysis by flow cytometry.

NG-343 and EnAd Selective Virus Replication

[0524] For qPCR, cell supernatants were collected and clarified by centrifuging for 5 mins, 1200 rpm. DNA was extracted from 10 .mu.l of supernatant using the Sigma Genelute DNA extraction Kit, according to the manufacturer's protocol. A standard curve using EnAd virus particles (2.5.times.10.sup.10 to 2.5.times.10.sup.5 vp) was also prepared and extracted using the Sigma Genelute Kit. Each extracted sample or standard was analysed by qPCR using an EnAd E3 gene specific primer-probe set.

[0525] Quantification of the number of detected virus genomes per cell demonstrated that NG-343 and EnAd virus replication was comparable in all cell lines analysed (FIG. 9A).

NG-343 Selective Transgene Expression

[0526] For detection of IFN.alpha. expression, cell supernatants were collected and clarified by centrifuging for 5 mins, 1200 rpm. Supernatants were diluted into 5% BSA/PBS assay buffer (1:2 or 1:50 or 1:100) and ELISA was carried out using the Verikine Human IFN alpha Kit (Pbl assay science) according to the manufacturer's protocol.

[0527] The concentrations of secreted IFN.alpha. were determined by interpolating from the standard curve. IFN.alpha. expression could only be detected in the supernatants of NG-343 infected HT-29 cells and was not detectable (less than the lower limit of quantitation [<LLOQ]) in either of the fibroblast cell lines, or the bronchial epithelial cell line (FIG. 9B).

[0528] For CD80 cell surface expression, cells were then either incubated at 5.degree. C. for 1 hr with buffer, mouse isotype control antibody conjugated to Cy5 or anti-human CD80 antibody conjugated to Cy5 (clone 2D10). All samples were also co-stained with Zombie Aqua live/dead to differentiate viable cells. Samples were washed 3 times with 1% BSA/PBS before analysis by flow cytometry (FACS, Attune) for cell viability and CD80 protein expression on the cell surface. In keeping with the IFN.alpha. expression data, CD80 expression could only be detected on HT-29 cells, with no detectable expression on either the fibroblast or bronchial epithelial cell lines (FIG. 9C).

[0529] Taken together these data demonstrated that both IFN.alpha. and CD80 transgenes are selectively expressed in cells permissive to EnAd virus infection i.e. carcinoma cells, and the encoding of transgenes does not alter the selectivity of the NG-343 virus when compared to the parental EnAd virus.

Example 10: Activity of NG-343 Transgene Expression on Immune Cell Activation

[0530] To determine if treatment of tumour cells with NG-343 virus could lead to enhanced innate immune cell responses compared to no treatment or to EnAd treatment, freshly isolated peripheral blood mononuclear cells (PBMCs) were co-cultured with tumour cells either infected with NG-343 or EnAd or left uninfected. Immune cell activation was assessed by flow cytometry analysis of innate immune cell populations or ELISA analysis of co-culture supernatants. Briefly, A549 lung carcinoma cells were seeded in 12 well plates at a density of 4.times.10.sup.5 cells/well. After 20 hrs cells were infected with 10 ppc of EnAd or NG-343 virus or left uninfected and then incubated for 24 hrs, 37 degrees, 5% C02. PBMCs isolated from a healthy human donor by density gradient centrifugation were then added to the A549 culture wells at a ratio of 5 PBMCs to 1 A549 cell. At 48 hrs post addition of PBMCs co-culture supernatants were harvested from the plates. To analyse dendritic cell activation at this point, cells were incubated at 5.degree. C. for 1 hr with buffer, mouse isotype control antibodies conjugated to Alexa Fluor 488, PE, PerCP/Cy5.5, BV605 or BV412, anti-CD14 antibody conjugated to Alexa Fluor 488, anti-CD80 antibody conjugated to PE, anti-HLA-DR conjugated to PerCP.Cy5.5, anti-CD3 conjugated to BV605 or anti-PD-L1 antibody conjugated to BV421. All samples were also co-stained with Zombie Aqua live/dead to differentiate viable cells. Samples were washed 3 times with 1% BSA/PBS before analysis by flow cytometry (FACS, Attune). Viable cells that stained negative for both CD14 and CD3 but positive for HLA-DR were defined as the dendritic cell population. Expression of the DC activation marker, CD80 and PD-L1 was compared on this population (FIG. 10). These analyses revealed that tumour cells infected with NG-343 could induce increased surface levels of both CD80 and PD-L1 on the surface of DCs when compared to EnAd infected or uninfected tumour cell culture.

Example 11: Activity of EnAd Virus, NG-347, Expressing Three Transgenes; the T Cell Activating Antigen CD80, the Chemokine MIP1.alpha. and the Cytokine IFN.alpha.

Characterisation of NG-347 Virus Activity Compared to EnAd in Carcinoma Cell Lines

[0531] CD80 transgene expression (assessed by flow cytometry) and IFN.alpha. or MIP1.alpha. (CCL3) transgene expression (assessed by ELISA) was compared in NG-347 and EnAd treated colon carcinoma cell line, HT-29 or lung carcinoma cell line, A549. NG-347 is a virus derived from EnAd that contains a transgene cassette encoding the human T cell activating antigen, CD80, the human cytokine Interferon alpha 2b and the human chemokine MIP1.alpha. (LD78s isoform). Transgene expression is under the control of the virus endogenous major late promoter. A schematic of the inserted cassette is shown in FIG. 3F. Production of NG-347 virus is detailed in Example 6. A549 or HT-29 carcinoma cell lines were seeded in 12 well plates at cell densities of 7.5.times.10.sup.5 cells/well for A549 cells or 1.4.times.10.sup.6 cells/well for HT-29 cells. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with 100 EnAd or NG-347 virus particles per cell (ppc) or were left uninfected. Assays were carried out 24, 48 or 72 hrs post infection.

Analysis of IFN.alpha. or MIP1.alpha. Expression by ELISA

[0532] Supernatants of HT-29 or A549 cells lines infected for 24, 48 or 72 hrs with 100 ppc of EnAd or NG-347 or left uninfected were analysed for expression of secreted IFN.alpha. or secreted MIP1.alpha. by ELISA.

[0533] Culture supernatants were prepared according to the methods detailed in Example 9. IFN.alpha. ELISA was carried out using the Verikine Human IFN alpha Kit (Pbl assay science) and MIP1.alpha. ELISA was carried out using the Human CCL3 Quantikine ELISA kit (R & D systems). Both assays were carried out according to the manufacturers' protocol.

[0534] The concentrations of secreted IFN.alpha. or MIP.alpha. were determined by interpolating from the standard curves. IFN.alpha. and MIP1.alpha. expression increased in the cellular supernatants over the course of infection and was detected for both HT-29 and A549 cells lines (FIG. 11A and FIG. 11B).

Analysis of CD80 Expression by Flow Cytometry

[0535] CD80 protein expression was compared on the surface of HT-29 and A549 cells at 48 hrs post-infection. Cells were harvested and stained according to methods detailed in example 9. Cells were analysed for cell viability and CD80 protein expression on the cell surface by flow cytometry. Analysis of CD80 expression at this time point on live cells showed CD80 could be detected on the surface of .about.-96% of NG-347 treated HT-29 cells and .about.-99% of NG-347 treated A549 cells but no staining was detected on EnAd treated controls (FIG. 11C).

Example 12: Activity of EnAd Virus, NG-345, Expressing Three Transgenes; the Cytokine Flt3 Ligand, the Chemokine Mip1.alpha. and the Cytokine IFN.alpha.

Characterisation of NG-345 Virus Activity Compared to EnAd in Carcinoma Cell Lines

[0536] Flt3 Ligand, IFN.alpha. and MIP1.alpha. transgene expression (assessed by ELISA) was compared in NG-345 and EnAd treated colon carcinoma cell line, HT-29 or lung carcinoma cell line, A549. NG-345 is a virus derived from EnAd that contains a transgene cassette encoding a soluble variant of human Flt-3 ligand, the human cytokine Interferon alpha 2b and the human chemokine MIP1.alpha. (LD78s isoform). Transgene expression is under the control of the virus endogenous major late promoter. A schematic of the inserted cassette is shown in FIG. 3D. Production of NG-345 virus is detailed in Example 4. A549 or HT-29 carcinoma cell lines were seeded in 12 well plates at cell densities of 7.5.times.10.sup.5 cells/well for A549 cells or 1.4.times.10.sup.6 cells/well for HT-29 cells. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with 100 EnAd or NG-345 virus particles per cell (ppc) or were left uninfected. Assays were carried out 24, 48 or 72 hrs post infection.

Analysis of FLt-3 Ligand, IFN.alpha. or MIP1.alpha. Expression by ELISA

[0537] Supernatants of HT-29 or A549 cells lines infected for 24, 48 or 72 hrs with 100 ppc of EnAd or NG-345 or left uninfected were analysed for expression of secreted Flt3-Ligand, secreted IFN.alpha. or secreted MIP1.alpha. by ELISA.

[0538] Culture supernatants were prepared according to the methods detailed in Example 9. IFN.alpha. ELISA was carried out using the Verikine Human IFN alpha Kit (Pbl assay science), MIP1.alpha. ELISA was carried out using the Human CCL3 Quantikine ELISA kit (R & D systems) and Flt3L ELISA was carried out using the Flt3L human ELISA kit (Abcam). All assays were carried out according to the manufacturers' protocol.

[0539] The concentrations of secreted IFN.alpha., MIP.alpha. or FLt3L were determined by interpolating from the standard curves. IFN.alpha., MIP1.alpha. and Flt3 L expression increased in the cellular supernatants over the course of infection and was detected in both HT-29 and A549 cells lines (FIG. 12A-C).

Example 13. Oncolytic Activity and Infectivity of NG-347 and NG-348 Viruses in Colon Carcinoma Cells

Virus Oncolytic Potency

[0540] HT-29 colon carcinoma cells were seeded in 96 well plates at a cell density of 2.5e4 cells/well. Plates were incubated for 4 hrs, 37.degree. C., 5% CO.sub.2, before cells were either infected with EnAd, NG-347 or NG-348 virus particles at an infection density range of 100-0.39 particles per cell (ppc). HT-29 cell viability was assessed using Cell Titre 96 MTS Reagent (Promega: G3581) 72 hrs post infection. Quantification of the % cell survival at each infection density demonstrated that NG-347 and NG-348 oncolytic potency was comparable to EnAd (FIGS. 13A and 13B).

Viral Particle Infectivity

[0541] HT-29 colon carcinoma cells were seeded in 12 well plates at a cell density of 4e5 cells/well. Plates were incubated for 24 hrs, 37.degree. C., 5% CO.sub.2, before cells were either infected with EnAd, NG-347 or NG-348 virus particles at an infection density range of 1.6e7-2e6 vp/mL. Infection of HT-29 cells was detected by antibody staining of the virus protein hexon. Stained cells were quantified by manual counting of 6 fields of view per well, across 6 replicate wells for each dilution tested. The particle to infectivity ratio (P:I) was calculated for each virus from the viral titre and demonstrated both NG-347 and NG-348 have similar infectivity ratios to EnAd reference controls (FIG. 13C).

Example 14. Cell Surface Expression of the T Cell Activating Antigen, CD80, in NG-347 and NG-348 Infected Carcinoma Cell Lines

[0542] CD80 transgene expression (assessed by flow cytometry) was compared in NG-347, NG-348 and EnAd treated colon carcinoma cell line, DLD-1 or lung carcinoma cell line, A549. A549 or DLD-1 carcinoma cell lines were seeded in 12 well plates at cell densities of 7.5e5 cells/well. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with, 10 EnAd, NG-348 or NG-347 virus particles per cell (ppc) or were left uninfected. CD80 protein expression was compared on the surface of A549 or DLD-1 cells at 24, 48, 72 or 96 hrs post-infection. At each time point cells were harvested and stained according to methods detailed in example 9. Cells were analysed for cell viability and CD80 protein expression at the cell surface by flow cytometry. Analysis of CD80 expression at 72 hrs post infection in A549 cells showed CD80 could be detected on the surface of >95% of NG-347 or NG-348 treated cells (FIGS. 14A to 14D). At 96 hrs post infection the virus treatments had lysed the majority of A549 cells therefore FACs analysis was not carried out. For DLD-1 cells expression could be detected on >50% of cells by 96 hrs post-treatment with NG-348 and >70% of cells following NG-347 treatment (FIGS. 15A to 15D). Staining was not detected on EnAd or untreated controls.

Example 15. T Cell Activation and Degranulation Mediated by NG-348 Infected Carcinoma Cell Lines

[0543] A549 lung carcinoma cells, either infected with NG-348 or EnAd virus particles or left uninfected, were co-cultured with T cells isolated from human PBMC donors. The selectivity of expression of NG-348 virus encoded CD80 was assessed on the surface of both A549 and T cells by flow cytometry. T cell activation was assessed by analysing cell surface activation markers (by Flow cytometry), CD107a cell surface expression as a marker for degranulation (by Flow cytometry) and secretion of stimulatory cytokines, IL-2 and IFN.gamma. (by ELISA).

[0544] A549 cells were seeded into 12 well plates at a density of 5e5 cells/well. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with 10 EnAd or NG-348 virus particles per cell (ppc) or were left uninfected. At 48 hrs post-infection CD3.sup.+ T cells, isolated by negative selection from PBMCs (MACs) were added to the A549 cell monolayers at a ratio of 8 T cells:1 tumour cell. The co-culture was carried out for 16 hrs, after which point cellular supernatants were collected for ELISA analysis and tumour cells and T cells harvested for Flow cytometry analysis.

[0545] Culture media containing non-adherent cells was removed from co-culture wells and centrifuged (300.times.g). The supernatant was carefully removed, diluted 1 in 2 with PBS 5% BSA and stored for ELISA analysis. The adherent cell monolayers were washed once with PBS and then detached using trypsin. The trypsin was inactivated using complete media and the cells were added to the cell pellets that had been collected from the culture supernatants. The cells were centrifuged (300.times.g), the supernatant discarded and the cell pellet washed in 200 .mu.L of PBS. The cells were centrifuged again then resuspended in 50 .mu.L of FACs buffer (5% BSA PBS) containing Live/Dead Aqua (Life tech) for 15 minutes at RT. The cells were washed once in FACs buffer before staining with panels of directly conjugated antibodies: anti-CD3 conjugated to BV605; anti-CD25 conjugated to BV421; anti-CD107a conjugated to FITC; anti-EpCam conjugated to PE or anti-CD4 conjugated to PE; and either anti-CD80 conjugated to PE/Cy5 or anti-HLA-DR conjugated to PE/Cy5. A sample of cells from each co-culture condition was also stained with relevant isotype control antibodies. All staining was carried out in FACs buffer in a total volume of 50 L/well for 15 minutes, 4.degree. C. Cells were then washed with FACs buffer (200 .mu.L) before resuspension in 200 L of FACs buffer and analysis by Flow cytometry (Attune).

Selective Expression of CD80

[0546] Similar to results shown in example 14, CD80 expression was detectable at the surface of >80% of NG-348 infected EpCam.sup.+ A549 cells but not EnAd infected or uninfected control cells (FIG. 16). In contrast CD3.sup.+ T cells showed no detectable expression of CD80 at the cell surface indicating, at least under these experimental conditions, transgene expression is selective for tumour cells in the co-culture.

Upregulation of T Cell Activation Markers

[0547] Flow cytometry analysis of T cell activation was assessed by expression of the T cell activation markers CD25 and HLA-DR on live, CD3.sup.+, single cells. These data showed that both the number of T cells expressing CD25 (FIGS. 17A and 17B) and the average level of CD25 expression on the T cell surface (FIG. 17C) were significantly higher for T cells cultured with NG-348 infected A549 cells than EnAd or uninfected controls. Specifically, there was no difference in T cell activation status when comparing untreated controls to EnAd (26.9%.+-.3.4% and 25.3.+-.3.5% of T cells expressing CD25, respectively) whereas CD25 was upregulated on the majority of cells co-cultured with NG-348 (83.2.+-.1.5%). CD25 expression was also analysed on CD4 and CD8 T cell subsets by gating the CD3.sup.+ T cells based on their expression of CD4. These analyses showed that CD25 expression is significantly upregulated on both CD4.sup.+ and CD4- T cell subsets in NG-348 treated co-cultures compared to EnAd and uninfected controls (FIGS. 18A to 18D).

[0548] In contrast to CD25 the number of cells expressing HLA-DR was low, <5%, for all conditions tested (FIG. 19A). This is likely due to the early time point after co-culture at which flow cytometry analysis was carried out. However, there was a slight but significant increase in the mean fluorescence intensity of HLA-DR staining CD3.sup.+HLA-DR.sup.+ cells from NG-348 treated co-cultures compared to controls (FIG. 19B).

Stimulation of T Cell Degranulation

[0549] Analysis of CD107a expression on the surface of live, CD3.sup.+ T cells showed a significant increase in the number of T cells which had degranulated and were therefore stained with CD107a, when A549 cells were infected with NG-348 (8.3%.+-.1.7% of cells) compared to either EnAd (0.6%.+-.0.2% of cells) or untreated controls (0.1%.+-.0.02% of cells) (FIG. 20A and FIG. 20B). Similar to CD25 upregulation, both CD4.sup.+ and CD4- T cell subsets showed significantly increased CD107a expression compared to EnAd or A549 controls (FIG. 21A to FIG. 21D).

Secretion of the Stimulatory Cytokines IL-2 and IFN.gamma.

[0550] For detection of IL-2 or IFN.gamma. expression, co-culture supernatants were diluted into 5% BSA/PBS assay buffer (in a range of 1:100 to 1:1000) and ELISA was carried out using the Human IL-2 Ready Set go Kit (Affymetrix) or Human IFN gamma Ready set go kit (Affymetrix) according to the manufacturer's protocol.

[0551] The concentrations of secreted IL-2 or IFN.gamma. were determined by interpolating from the standard curves. Expression of IL-2 could only be detected in the supernatants of co-cultures using NG-348 infected A549 cells and was not detectable in either the EnAd, or untreated controls (FIG. 22A). Expression of IFN.gamma. could also be detected, at very high levels (>300 ng/mL) in supernatants of co-cultures from NG-348 infected A549 cells, which was significantly higher that either EnAd or untreated controls (FIG. 22B).

Example 16. T Cell Activation of CD4 and CD8 T Cells can be Independently Mediated by NG-348 Infected Carcinoma Cell Lines

[0552] A549 lung carcinoma cells infected with NG-348 or EnAd virus particles or left uninfected, were co-cultured with either CD4.sup.+ T cells or CD8.sup.+ T cells isolated from human PBMC donors. T cell activation was assessed by the secretion of the stimulatory cytokine IFN.gamma. into culture supernatants.

[0553] A549 cells were seeded and infected with NG-348 or EnAd virus particles or left uninfected according to the methods detailed in Example 14. 48 hrs post infection CD4.sup.+ T cells or CD8.sup.+ T cells isolated by negative selection from a PBMC donor were added to the A549 cell monolayer at a ratio of 8 T cells to 1 tumour cells. After 16 hrs of co-culture supernatants were harvested and assessed for IFN.gamma. according to the methods detailed in Example 14.

[0554] For CD4.sup.+ T cells Expression of IFN.gamma. was only detected in supernatants of co-cultures from NG-348 infected A549 cells and was not detectable in either the EnAd or untreated controls (FIG. 23A). For CD8.sup.+ T cells expression of IFN.gamma. was detected at significantly higher levels for NG-348 infected A549 cells than for EnAd or untreated controls (FIG. 23B), demonstrating that both CD8 and CD4 cells can be activated to secret IFN.gamma. by NG-348 virus activity in tumour cell lines.

Example 17. T Cell Activation Mediated by NG-347 Infected Carcinoma Cell Lines

[0555] A549 lung carcinoma cells, either infected with NG-347 or EnAd virus particles or left uninfected, were co-cultured with T cells isolated from human PBMC donors. T cell activation was assessed by analysing cell surface activation markers (by Flow cytometry) and secretion of the stimulatory cytokine, IFN.gamma. (by ELISA analysis of cellular supernatants).

[0556] A549 cells were seeded into 12 well plates at a density of 5e5 cells/well. Plates were incubated for 18 hrs, 37.degree. C., 5% C02, before cells were either infected with 10 EnAd or NG-347 virus particles per cell (ppc) or were left uninfected. At 24 hrs post-infection CD3.sup.+ T cells, isolated by negative selection from PBMCs (MACs) were added to the A549 cell monolayers at a ratio of 5 T cells:1 tumour cell. The co-culture was carried out for 48 hrs, before cellular supernatants were collected for ELISA analysis and tumour cells and T cells harvested for Flow cytometry analysis according to the methods detailed in EG 15. The harvested cells were stained with directly conjugated antibodies: anti-CD3 conjugated to BV605 and anti-CD69 conjugated to BV421. A sample of cells from each co-culture condition was also stained with relevant isotype control antibodies. All staining was carried out in FACs buffer in a total volume of 50 L/well for 15 minutes, 4.degree. C. Cells were then washed with FACs buffer (200 L) before resuspension in 200 L of FACs buffer and analysis by Flow cytometry (Attune).

Upregulation of T Cell Activation Marker, CD69

[0557] Flow cytometry analysis of T cell activation was assessed by expression of the T cell activation marker CD69 on live, CD3.sup.+, single cells. These data showed that the number of T cells expressing CD69 was significantly higher for T cells cultured with NG-347 infected A549 cells than EnAd or uninfected controls (FIGS. 24A and 24B).

Secretion of the Stimulatory Cytokine IFN.gamma.

[0558] For detection of IL-2 or IFN.gamma. expression, co-culture supernatants were diluted into 5% BSA/PBS assay buffer (in a range of 1:100 to 1:1000) and ELISA was carried out using the Human IFN gamma Ready set go kit (Affymetrix) according to the manufacturer's protocol.

[0559] The concentration of secreted IFN.gamma. was determined by interpolating from the standard curve. Expression of IFN.gamma. could only be detected in the supernatants of co-cultures using NG-347 infected A549 cells and was not detectable in either the EnAd, or untreated controls (FIG. 25).

Example 18: Production of EnAd Viruses Expressing the T Cell Activating Antigen CD80 and a Membrane-Anchored Single Chain Fv Fragment Antibody to the E Chain of the Human CD3 Complex (CD3E)

[0560] The plasmid pEnAd2.4 was used to generate the plasmids pNG-348A by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO 11) and a membrane-anchored chimeric form of the single chain Fv anti-human CD3e with a C-terminal V5 tag (SEQ ID NO: 99). The pNG-348 cassette contains; a 5' short splice acceptor sequence (SEQ ID NO. 2); membrane-anchored anti-human CD3e ScFv cDNA; a C-terminal V5 tag (SEQ ID NO: 100); a high efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); human CD80 cDNA sequence and a 3' polyadenylation sequence (SEQ ID NO: 5). A Schematic of the NG-348A transgene cassettes is shown in FIG. 26A. Construction of the plasmid is confirmed by DNA sequencing.

Virus Production and Characterisation

[0561] The plasmid pNG-348A is linearised by restriction digest with the enzyme AscI to produce the virus genome NG-348A (SEQ ID NO: 101). The virus NG-348A is amplified and purified according to methods detailed in Example 1.

Example 19: Production of EnAd Viruses a Membrane-Anchored Single Chain Fv Fragment Antibody to the E Chain of the Human CD3 Complex (CD3e)

[0562] The plasmid pEnAd2.4 was used to generate the plasmids pNG-420 and pNG-420A by direct insertion of a cassettes encoding a membrane-anchored chimeric form of the single chain Fv anti-human CD3e with a C-terminal V5 tag (SEQ ID NO: 99) or without a V5 tag (SEQ ID NO: 15). The pNG-420 cassette contains; a 5' short splice acceptor sequence CAGG; membrane-anchored anti-human CD3e scFv cDNA and a 3' polyadenylation sequence (SEQ ID NO: 5). The pNG-420A cassette contains; a 5' short splice acceptor sequence cagg; membrane-anchored anti-human CD3e ScFv cDNA; a C-terminal V5 tag (SEQ ID NO: 100) and a 3' polyadenylation sequence (SEQ ID NO: 5). Schematics of the NG-420 and NG-420A transgene cassettes are shown in FIGS. 26B and 26C. Construction of each plasmid is confirmed by DNA sequencing.

Virus Production and Characterisation

[0563] The plasmids pNG-420 and pNG-420A are linearised by restriction digest with the enzyme AscI to produce the virus genomes NG-420 (SEQ ID NO: 102) and NG-420A (SEQ ID NO: 103). The viruses NG-420 and NG-420A are amplified and purified according to methods detailed in Example 1.

Example 20

[0564] A549 human lung carcinoma cells and MRC5 human fibroblast cells were cultured with EnAd, NG-347 or NG-348 viruses (at 10 ppc) to compare virus genome replication, virus hexon and transgene expression by these cell types. After 72 hours culture, cells were either stained for FACS analyses of surface markers or supernatants and cell lysates prepared for virus genome replication (qPCR) or mRNA (RT-qPCR) analyses of hexon or transgene expression.

[0565] Virus genome replication and hexon mRNA expression for the two transgene bearing viruses, NG-347 and NG-348 were equivalent to those for the parental virus, EnAd (FIG. 27). For NG-348 (FIG. 28), CD80 and anti-human CD3-scFv transgene mRNA expression levels were high with A549 tumour cells, with only a low level signal for the non-tumour MRC5 cells. CD80 protein expression on the surface of cells assessed by FACS was detected on the majority of NG-348 treated A549 cells but was not detectable on MRC5 cells, with no CD80 detected on either cell type left untreated or treated with EnAd. Similarly, CD80 transgene mRNA and protein expression following NG-347 treatment was selectively detected in A549 tumour cells not MRC5 cells (FIG. 29).

[0566] For EnAd and NG-347 treated cell cultures, levels of MIP1.alpha. and IFN.alpha. mRNA in cell lysates and secreted proteins in supernatants were measured by RT-qPCR and specific ELISAs, respectively. Data (FIG. 30) show selective expression of both transgenes by A549 tumour cells, with no detectable MIP1.alpha. chemokine or IFN.alpha. cytokine in MRC5 supernatants.

Example 21

[0567] The selectivity/activity of EnAd, NG-347 and NG-348 viruses with human T-cells was evaluated by culturing isolated CD3.sup.+ T cells for 3 days with either 500 ppc or 5000 ppc of each virus. Selectivity/activity was assessed by a) flow cytometry analysis of T cells stained with antibodies targeting CD69, CD4, CD80, CD25 and CD3, b) ELISA analysis of human MIP1.alpha., IFN.alpha. and IFN.gamma. protein secretion, c) qPCR analysis of virus replication and d) RT-qPCR analysis of gene expression.

[0568] As shown in FIG. 31, T-cells were not supportive of virus genome replication for any of the viruses tested with only background signals in the virus hexon RT-qPCR assay. A549 tumour cells supported high levels of hexon mRNA expression. RT-qPCR analyses for transgene mRNA expression by T-cells showed only background signals (<1 copy/cell) for CD80 by both NG-347 and NG-348, and a similar lack of significant expression of anti-CD3-ScFv mRNA by NG-348, despite the high virus exposure (5000 ppc). High levels of expression of both transgenes were detected with treated (10 ppc) A549 tumour cells (FIGS. 32 & 33). Expression of IFN.alpha. and MIP1.alpha. transgene mRNA was also selectively detected by NG-347 (not EnAd) treated A549 tumour cells (at 10 ppc) and not by T-cells treated with 5000 ppc (FIG. 34). In addition, CD80 cell surface protein expression was only detectable with A549 cells not T-cells for both NG-347 and NG-348 (FIGS. 32 & 33). EnAd treatment did not lead to CD80 expression by either cell type, and A549 cell death (as assessed by dye uptake) was similarly high for all three viruses; a low level of non-specific T-cell death was induced by all viruses due to the very high levels of virus particles used in the experiment (FIGS. 32 & 33). Similar transgene mRNA and protein expression data were obtained when viruses were used at 500 ppc (data not shown).

[0569] In the absence of tumour cells, purified human T-cells were not activated to upregulate activation markers CD25 or CD69 when cultured with any of the viruses (Table 5).

TABLE-US-00008 TABLE 5 Lack of expression of activation markers CD25 and CD69 by purified human CD3.sup.+ T-cells treated with 5000 ppc of different viruses Untreated EnAd NG-347 NG-348 CD25.sup.+ CD4 T-cells 30.7 24.6 23.4 23.3 CD69.sup.+ CD4 T-cells 0.1 0.4 0.3 0.7 CD25.sup.+ CD8 T-cells 5.9 4.7 4.1 4.1 CD69.sup.+ CD8 T-cells 0.5 1.0 0.9 1.3

Example 22

[0570] A similar virus selectivity experiment to that described in Example 21 was carried out using unseparated human PBMCs rather than purified T-cells, including making the same activity assessments. As with human T-cells in example 21, the data from this study collectively demonstrate lack of virus replication and transgene expression by human PBMCs. FIGS. 35-37 show data using 5000 ppc of EnAd, NG-347 or NG-348, but similar data was generated using 500 ppc (not shown). FIG. 35 shows virus genome replication and hexon mRNA expression and FIGS. 36 & 37 show transgene mRNA expression. Assay backgrounds were set according to signals generated in the assay with the respective virus spiked into culture media and then processed in the same way as for the cell lysate samples. There was no detectable expression of CD80 transgene on CD3+ T-cells or CD40+ cells (primarily B-cells) in these PBMC cultures with any of the viruses (not shown).

[0571] NG-347 and NG-348 virus particle-mediated activation of innate immune cells (monocytes, DCs) in the PBMC cultures were similar to those of EnAd, as shown in FIGS. 38A and 38B and FIGS. 39A and 39B for downregulation of CD14 expression and upregulation of HLA-DR and endogenous cell surface CD80, as well as secretion of MIP1.alpha. and IFN.alpha. (note that despite NG-347 encoding both of these molecules in its genome there was no increase in production levels over those for EnAd and NG-348 which do not encode the transgenes).

Example 23

[0572] This example is similar in design to experiments in examples 15-17, 21 and 22 but in these studies, the human PBMCs or purified T-cells were co-cultured with virus pre-treated (48 hours) A549 tumour cells or MRC5 fibroblasts. A549 or MRC5 cells were treated with 10 ppc of EnAd, NG-347, NG-348 or left untreated (UTC) and cultured for 48 hours to allow sufficient time for virus replication and any transgene expression. PBMCs or T-cells were then added to the cultures and left for 24 or 48 hours to evaluate the ability of virus treated cells to activate T-cells.

[0573] FIG. 40 shows virus genome replication data showing comparable replication of the three viruses in PBMC or T-cell co-cultures with both cell types, replication levels being high with A549 tumour cells and low with MRC5 fibroblasts.

[0574] T-cell activation as measured by upregulation of CD25 surface expression and CD8 effector T-cell degranulation, as measured by upregulation of CD107a on the cell surface, and IFN.gamma. production measured by intracellular cytokine staining were all selectively stimulated by NG-348 treated A549 cells compared to EnAd, with no stimulation mediated with MRC co-cultures (Table 6).

TABLE-US-00009 TABLE 6 Flow cytometry analyses of activation of human CD3+T-cells in T-cell and PBMC co-cultures with viruses Cells Treatment % CD25.sup.+ % CD8.sup.+CD107a.sup.+ % IFN.gamma..sup.+ A549 + T-cells Untreated 37.5 0.1 0.1 A549 + T-cells EnAd 38.4 0.1 0.2 A549 + T-cells NG-348 88.2 17.9 12.0 MRC5 + T-cells Untreated 38.8 0.3 0.4 MRC5 + T-cells EnAd 38.9 0.2 0.4 MRC5 + T-cells NG-348 39.1 0.3 0.3 A549 + PBMCs Untreated 28.3 ND ND A549 + PBMCs EnAd 29.4 ND ND A549 + PBMCs NG-348 73.7 ND ND MRC5 + PBMCs Untreated 23.0 ND ND MRC5 + PBMCs EnAd 23.3 ND ND MRC5 + PBMCs NG-348 21.7 ND ND ND = Not determined IFN.gamma. secretion into co-culture supernatants was also quantified by ELISA. The data (Figure 41) similarly demonstrate selective activation of T-cells co-cultured with NG-348 treated A549 tumour cells not MRC5 fibroblasts, with either purified T-cells or PBMCs used in the assays.

[0575] Ability of NG-347 to activate T-cells was also assessed by measuring CD69 levels on T-cells from co-cultures of either purified T-cells or PBMCs with A549 tumour cells or MRC5 fibroblasts. As shown in Table Z, a small enhancement in CD69 positive T-cells was seen with NG-347 treatment of A549 tumour cells compared to EnAd, which itself leads to upregulation of this early activation marker. These effects were not seen in MRC5 co-cultures. No CD80 expression was detected on the T-cells (not shown).

TABLE-US-00010 TABLE 7 CD69 expression on T-cells from NG-347 or EnAd treated co-cultures Cells Treatment % CD69+ A549 + T-cells Untreated 2.1 A549 + T-cells EnAd 18.7 A549 + T-cells NG-348 35.0 MRC5 + T-cells Untreated 3.8 MRC5 + T-cells EnAd 3.6 MRC5 + T-cells NG-348 4.4 A549 + PBMCs Untreated 1.2 A549 + PBMCs EnAd 19.1 A549 + PBMCs NG-348 28.7 MRC5 + PBMCs Untreated 2.6 MRC5 + PBMCs EnAd 2.7 MRC5 + PBMCs NG-348 3.9 In a separate experiment, A549 cells treated with NG-347 and co-cultured with human CD3+ T-cells led to upregulation of CD69 activation marker on the T-cells and secretion of IFN.gamma. (see Figures 24 & 25).

Example 24

[0576] CD14+ monocytic cells were isolated from PBMCs by antibody coated magnetic bead separation and cultured with human IL-4 and GM-CSF to differentiate them into dendritic cells. After 3 days of culture, the cells were treated with EnAd, NG-347 or NG-348 at 5000 ppc or left untreated. As a positive activation control, some cells were stimulated with LPS. Two days later supernatants were taken for cytokine ELISAs and cells were stained for surface activation marker expression and analysed by flow cytometry. As shown in table 8 all viruses induced upregulation of the costimulatory molecules CD80 and CD86, indicating that this previously identified particle-mediated innate immune cell activation effect was not altered by the transgene incorporation into the genomes of NG-347 and NG-348. All viruses also stimulated secretion of similar levels of MIP1.alpha. and IFN.alpha. (FIG. 42).

TABLE-US-00011 TABLE 8 Particle-mediated activation of human dendritic cells by EnAd, NG-347 and NG-348 DC treatment % CD80.sup.+ % CD86.sup.+ Untreated 3.0 10.4 EnAd 81.6 99.3 NG-347 82.1 99.4 NG-348 62.5 99.5 LPS positive control 97.5 98.5

Example 25

[0577] In a set of experiments, JurkatDual cells were used in co-cultures with tumour cells as a T-cell activation reporter assay for assessing functionality of transgene expression by NG-347, NG-348 and NG-420 viruses, with EnAd serving as a negative control. JurkatDual cells stably express two different reporter genes: an NF .kappa.B reporter gene producing a secreted form of luciferase which is responsive to signalling via the T-cell receptor complex and an IFN.alpha.-responsive secreted alkaline phosphatase (SEAP) reporter gene. A549 cells were pre-cultured with viruses at '10 ppc for two days, and then JurkatDual cells were added for overnight co-culture (18-24 h) and then supernatants collected for assay of luciferase and SEAP activities. As shown in FIG. 43, NG-347 infected A549 cells selectively induced SEAP production, which aligns with their production of IFN.alpha. (see FIG. 11) but did not induce luciferase activity. In contrast, NG-348 which expresses the membrane anti-CD3-ScFv to activate the T-cell receptor complex induced luciferase but not SEAP.

[0578] In another experiment A549 lung carcinoma cells and HCT-116, HT-29 & DLD colon carcinoma cells were pre-cultured for 48 hours with 10 ppc of EnAd, NG-347, NG-348 or NG-420 viruses before co-culturing with JurkatDual cells overnight, with supernatants tested for levels of luciferase to indicate level of activation induced. As shown in FIG. 44, all four tumour cell types cultured with NG-348 or NG-420 viruses, which encode cell surface anti-CD3-ScFv, activated the JurkatDual cells whereas EnAd and NG-347 did not, with levels of luciferase similar to that of uninfected tumour cell controls (UIC).

[0579] In another experiment, A549 or HT-29 tumour cells were pre-cultured with different amounts of either NG-348 or NG-420 before adding the JurkatDual cells and measuring their luciferase secretion. The data in FIG. 45 show that activation of the NF.kappa.B activity in JurkatDual cells is dependent on the dose of virus used to treat the tumour cells with.

Example 26

[0580] The in vivo pharmacokinetic, biodistribution and particle-mediated systemic cytokine induction activities of EnAd and NG-348 following IV dosing in immunocompetent CD1 mice were compared, Mice were dosed intravenously with 5.times.10.sup.9 particles of either EnAd or NG-348 and bled 2, 10, 30, 60 and 120 minutes post dosing. Whole blood was DNA extracted and analysed by qPCR for levels of virus genome (FIG. 46). Clearance of both viruses from the blood followed similar kinetics. Similarly, the induction of MCP-1 cytokine response (a measure of particle-mediated activation of innate immune such as liver Kupffer cells) was also similar for both viruses, as were the tissue biodistribution patterns (FIG. 46).

Example 27

[0581] CB17 SCID mice were implanted subcutaneously with HCT116 cells and injected intratumourally (IT) or intravenously (IV) with EnAd, NG-347 or NG-348 viruses (5.times.10.sup.9 virus particles), or control, once tumours were greater than 70 mm.sup.3. For the IV dosed mice, blood samples were taken from three mice from each group 3, 15 and 30 minutes after IV dosing, DNA extracted and the level of virus genomes in the blood assessed by qPCR (pharmacokinetics [PK] analysis). Data (FIG. 47) show that NG-347 and NG-348 have similar PK to EnAd (and to each other). After 6 hours, tumours, livers, lungs and spleens were resected from 3 mice from each group. Homogenised tissues were DNA extracted and analysed for level of virus genomes by qPCR (biodistribution analysis). Data (FIG. 48A) show similar tissue biodistribution for the three viruses. After 7 days or 14-21 days, tumours were excised from three mice from each group and homogenized to produce a tumour lysate which was used to prepare both DNA and RNA. Level of virus genomes in the tumours at the two time points were measured by qPCR analyses of the extracted DNA. Data (FIG. 48B) show that tumours from both IV and IT dosed mice have levels of virus genomes higher than the amount of virus dosed, indicating virus replication in the tissue, with IT dosing giving higher genome levels than IV at day 7, but both being similarly high at the 14-21 day timeframe. All three viruses replicated to similar levels.

[0582] Similarly, levels of virus hexon mRNA in tumour lysates detected by RT-qPCR were comparable between EnAd, NG-347 and NG-348 at both time points tested (FIGS. 49 and 50). Similar levels of anti-CD3-ScFv and CD80 mRNA were detected at both time points and both dosing routes for NG-348 treatment, with only assay background readings with EnAd dosing (FIGS. 50 & 51). MIP1.alpha. and IFN.alpha. mRNA levels were also selectively detected following NG-347 dosing, either IT or IV (FIG. 52).

[0583] Levels of CD80 protein encoded by both NG-347 and NG-348, and MIP1.alpha. protein encoded by NG-347 were measured in tumour lysates using specific ELISAs. The data in FIG. 53 show that following the single IV virus dose, both proteins could also be detected selectively in tumour extracts. Neither protein was detected in blood samples from the same mice.

Example 28

[0584] To evaluate the activity and tumour cell dependency of NG-348 virus in vivo, different combination of human PBMCs (5.times.10.sup.7 cells), A549 human tumour cells (5.times.10.sup.6) and either EnAd or NG-348 (at 5.times.10.sup.9 ppc) were injected into the peritoneum of immune-deficient SCID-beige mice, with viruses or control (saline) being dosed within 15 minutes after injection of the cells. After 3 days, the peritoneal cavity was lavaged with 5 mL of saline and recovered cells were analysed by flow cytometric analyses with a panel of T-cell activation markers (CD25, CD69 and HLA-DR) to assess levels of T-cell activation, following gating on the CD3+ T-cell population. Data from two separate experiments (Table 9) demonstrate that NG-348 selectively leads to human T-cell activation in vivo in a tumour cell dependent manner.

TABLE-US-00012 TABLE 9 In vivo activation of human T-cells in A549 tumour bearing mice by NG-348 % % % % Group Virus Tumour N CD25.sup.+ CD69.sup.+ % DR.sup.+ CD25.sup.+, CD69.sup.+ CD25.sup.+, DR.sup.+ Experiment 1 1 EnAd Saline 2 1.9, 2.3 1.6, 3.0 7.7, 9.1 0.2, 0.5 0.3, 0.6 2 EnAd 5 .times. 10.sup.6 2 4.2, 2.9 6.2, 5.5 8.4, 8.4 0.8, 0.3 1.4, 0.4 A549 cells 3 NG-348 Saline 1 3.4 2.6 9.2 0.5 0.8 4 NG-348 5 .times. 10.sup.6 2 35.8, 36.6 50.4, 42.2 26.3, 19.2 22.4, 18.0 16.4, 12.2 A549 cells Experiment 2 1 Saline Saline 1 25.6 37.3 14.8 14.1 7.08 2 EnAd Saline 2 6.5, 7.3 17.8, 18.2 5.50, 6.1 3.58, 3.46 1.01, 1.49 3 NG-348 Saline 2 10.2, 6.5 26.7, 18.3 7.7, 6.0 6.73, 3.61 2.16, 1.44 4 Saline 5 .times. 10.sup.6 2 28.4, 22.7 54.4, 51.1 13.3 22.3 8.54, 7.72 A549 cells 15.0 17.5 5 EnAd 5 .times. 10.sup.6 1 13.2 29.4 5.1 7.84 1.62 A549 cells 6 NG-348 5 .times. 10.sup.6 3 34.4, 29.6, 56.4 58.9, 59.2, 85.0 12.5 27.2, 23.3, 9.07 A549 cells 9.8, 17.0 52.7 7.5, 14.2

Sequence CWU 1

1

109135DNAArtificial SequenceBy DNA sequence corresponding to and including bp 29345-29379 of the EnAd genome. 1caaataaagt ttaacttgtt tatttgaaaa tcaat 35248PRTArtificial SequencePDGF TM domain 2Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser Leu1 5 10 15Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val Leu 20 25 30Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Pro Arg 35 40 45314DNAArtificial SequenceSPLICE ACCEPTOR SEQUENCE 3tttctctctt cagg 14426DNAArtificial SequenceSPLICE ACCEPTOR SEQUENCE 4tgctaatctt cctttctctc ttcagg 265192DNAArtificial Sequencepoly adenylation sequence (SV40 late polyA sequence) 5cagacatgat aagatacatt gatgagtttg gacaaaccac aactagaatg cagtgaaaaa 60aatgctttat ttgtgaaatt tgtgatgcta ttgctttatt tgtaaccatt ataagctgca 120ataaacaagt taacaacaac aattgcattc attttatgtt tcaggttcag ggggaggtgt 180gggaggtttt tt 1926551DNAArtificial SequenceInternal Ribosome Entry Sequence (IRES) 6cgttactggc cgaagccgct tggaataagg ccggtgtgcg tttgtctata tgttattttc 60caccatattg ccgtcttttg gcaatgtgag ggcccggaaa cctggccctg tcttcttgac 120gagcattcct aggggtcttt cccctctcgc caaaggaatg caaggtctgt tgaatgtcgt 180gaaggaagca gttcctctgg aagcttcttg aagacaaaca acgtctgtag cgaccctttg 240caggcagcgg aaccccccac ctggcgacag gtgcctctgc ggccaaaagc cacgtgtata 300agatacacct gcaaaggcgg cacaacccca gtgccacgtt gtgagttgga tagttgtgga 360aagagtcaaa tggctcccct caagcgtatt caacaagggg ctgaaggatg cccagaaggt 420accccattgt atgggatctg atctggggcc tcggtgcaca tgcttttcat gtgtttagtc 480gaggttaaaa aacgtctagg ccccccgaac cacggggacg tggttttcct ttgaaaaaca 540cgatgataat a 551722PRTArtificial SequenceHigh efficiency self-cleavable P2A peptide sequence 7Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val1 5 10 15Glu Glu Asn Pro Gly Pro 20821PRTArtificial SequenceHigh efficiency self-cleavable F2A peptide sequence 8Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu1 5 10 15Glu Asn Pro Gly Pro 20923PRTArtificial SequenceHigh efficiency self-cleavable E2A peptide sequence 9Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp1 5 10 15Val Glu Ser Asn Pro Gly Pro 201025PRTArtificial SequenceHigh efficiency self-cleavable T2A peptide sequence 10Gly Ser Gly Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala1 5 10 15Gly Asp Val Glu Ser Asn Pro Gly Pro 20 2511288PRTArtificial SequenceHuman CD80 amino acid sequence 11Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr1 5 10 15Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys 20 25 30Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu 35 40 45Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile 50 55 60Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp65 70 75 80Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr 85 90 95Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly 100 105 110Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg 115 120 125Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr 130 135 140Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile145 150 155 160Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu 165 170 175Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp 180 185 190Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met 195 200 205Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg 210 215 220Val Asn Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro225 230 235 240Asp Asn Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly 245 250 255Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg 260 265 270Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val 275 280 28512188PRTArtificial SequenceHuman Interferona amino acid sequence 12Met Ala Leu Thr Phe Ala Leu Leu Val Ala Leu Leu Val Leu Ser Cys1 5 10 15Lys Ser Ser Cys Ser Val Gly Cys Asp Leu Pro Gln Thr His Ser Leu 20 25 30Gly Ser Arg Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser 35 40 45Leu Phe Ser Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu 50 55 60Glu Phe Gly Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His65 70 75 80Glu Met Ile Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser 85 90 95Ala Ala Trp Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr 100 105 110Gln Gln Leu Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val 115 120 125Thr Glu Thr Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys 130 135 140Tyr Phe Gln Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro145 150 155 160Cys Ala Trp Glu Val Val Arg Ala Glu Ile Met Arg Ser Phe Ser Leu 165 170 175Ser Thr Asn Leu Gln Glu Ser Leu Arg Ser Lys Glu 180 18513179PRTArtificial SequenceHuman soluble Flt3 ligand amino acid sequence 13Met Thr Val Leu Ala Pro Ala Trp Ser Pro Thr Thr Tyr Leu Leu Leu1 5 10 15Leu Leu Leu Leu Ser Ser Gly Leu Ser Gly Thr Gln Asp Cys Ser Phe 20 25 30Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu 35 40 45Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu 50 55 60Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln65 70 75 80Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly 85 90 95Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala 100 105 110Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser 115 120 125Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp 130 135 140Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro145 150 155 160Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala 165 170 175Thr Ala Pro1493PRTArtificial SequenceHuman Macrophage Inflammatory protein 1a amino acid sequence (LD78b isoform) 14Met Gln Val Ser Thr Ala Ala Leu Ala Val Leu Leu Cys Thr Met Ala1 5 10 15Leu Cys Asn Gln Val Leu Ser Ala Pro Leu Ala Ala Asp Thr Pro Thr 20 25 30Ala Cys Cys Phe Ser Tyr Thr Ser Arg Gln Ile Pro Gln Asn Phe Ile 35 40 45Ala Asp Tyr Phe Glu Thr Ser Ser Gln Cys Ser Lys Pro Ser Val Ile 50 55 60Phe Leu Thr Lys Arg Gly Arg Gln Val Cys Ala Asp Pro Ser Glu Glu65 70 75 80Trp Val Gln Lys Tyr Val Ser Asp Leu Glu Leu Ser Ala 85 9015322PRTArtificial SequenceMembrane anchored form of the anti-human CD3 single chain Fv 15Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly1 5 10 15Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg 20 25 30Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn65 70 75 80Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser 85 90 95Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp 115 120 125Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 130 135 140Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser145 150 155 160Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys 165 170 175Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser 180 185 190Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser 195 200 205Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser 210 215 220Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys225 230 235 240Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu 245 250 255Glu Ile Asn Arg Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 260 265 270Asn Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser 275 280 285Leu Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val 290 295 300Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys305 310 315 320Pro Arg1633493DNAArtificial SequenceNG-330 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes the T lymphocyte activation antigen, CD80, inserted in the region By. The transgene cassette contains a 5' SSA, human CD80 cDNA sequence and a 3' poly(A) 16tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg

attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta

gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc caccatgggc cacacacgga ggcagggaac 29400atcaccatcc aagtgtccat acctcaattt ctttcagctc ttggtgctgg ctggtctttc 29460tcacttctgt tcaggtgtta tccacgtgac caaggaagtg aaagaagtgg caacgctgtc 29520ctgtggtcac aatgtttctg ttgaagagct ggcacaaact cgcatctact ggcaaaagga 29580gaagaaaatg gtgctgacta tgatgtctgg ggacatgaat atatggcccg agtacaagaa 29640ccggaccatc tttgatatca ctaataacct ctccattgtg atcctggctc tgcgcccatc 29700tgacgagggc acatacgagt gtgttgttct gaagtatgaa aaagacgctt tcaagcggga 29760acacctggct gaagtgacgt tatcagtcaa agctgacttc cctacaccta gtatatctga 29820ctttgaaatt ccaacttcta atattagaag gataatttgc tcaacctctg gaggttttcc 29880agagcctcac ctctcctggt tggaaaatgg agaagaatta aatgccatca acacaacagt 29940ttcccaagat cctgaaactg agctctatgc tgttagcagc aaactggatt tcaatatgac 30000aaccaaccac agcttcatgt gtctcatcaa gtatggacat ttaagagtga atcagacctt 30060caactggaat acaaccaagc aagagcattt tcctgataac ctgctcccat cctgggccat 30120taccttaatc tcagtaaatg gaatttttgt gatatgctgc ctgacctact gctttgcccc 30180aagatgcaga gagagaagga ggaatgagag attgagaagg gaaagtgtac gccctgtata 30240agctagcttg actgactgag atacagcgta ccttcagctc acagacatga taagatacat 30300tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 30360ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 30420caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaaagcaa 30480gtaaaacctc tacaaatgtg gtagtcgtca gctatcctgc aggaacttgt ttatttgaaa 30540atcaattcac aaaatccgag tagttatttt gcctccccct tcccatttaa cagaatacac 30600caatctctcc ccacgcacag ctttaaacat ttggatacca ttagatatag acatggtttt 30660agattccaca ttccaaacag tttcagagcg agccaatctg gggtcagtga tagataaaaa 30720tccatcggga tagtctttta aagcgctttc acagtccaac tgctgcggat gcgactccgg 30780agtctggatc acggtcatct ggaagaagaa cgatgggaat cataatccga aaacggtatc 30840ggacgattgt gtctcatcaa acccacaagc agccgctgtc tgcgtcgctc cgtgcgactg 30900ctgtttatgg gatcagggtc cacagtgtcc tgaagcatga ttttaatagc ccttaacatc 30960aactttctgg tgcgatgcgc gcagcaacgc attctgattt cactcaaatc tttgcagtag 31020gtacaacaca ttattacaat attgtttaat aaaccataat taaaagcgct ccagccaaaa 31080ctcatatctg atataatcgc ccctgcatga ccatcatacc aaagtttaat ataaattaaa 31140tgacgttccc tcaaaaacac actacccaca tacatgatct cttttggcat gtgcatatta 31200acaatctgtc tgtaccatgg acaacgttgg ttaatcatgc aacccaatat aaccttccgg 31260aaccacactg ccaacaccgc tcccccagcc atgcattgaa gtgaaccctg ctgattacaa 31320tgacaatgaa gaacccaatt ctctcgaccg tgaatcactt gagaatgaaa aatatctata 31380gtggcacaac atagacataa atgcatgcat cttctcataa tttttaactc ctcaggattt 31440agaaacatat cccagggaat aggaagctct tgcagaacag taaagctggc agaacaagga 31500agaccacgaa cacaacttac actatgcata gtcatagtat cacaatctgg caacagcggg 31560tggtcttcag tcatagaagc tcgggtttca ttttcctcac aacgtggtaa ctgggctctg 31620gtgtaagggt gatgtctggc gcatgatgtc gagcgtgcgc gcaaccttgt cataatggag 31680ttgcttcctg acattctcgt attttgtata gcaaaacgcg gccctggcag aacacactct 31740tcttcgcctt ctatcctgcc gcttagcgtg ttccgtgtga tagttcaagt acaaccacac 31800tcttaagttg gtcaaaagaa tgctggcttc agttgtaatc aaaactccat cgcatctaat 31860cgttctgagg aaatcatcca agcaatgcaa ctggattgtg tttcaagcag gagaggagag 31920ggaagagacg gaagaaccat gttaattttt attccaaacg atctcgcagt acttcaaatt 31980gtagatcgcg cagatggcat ctctcgcccc cactgtgttg gtgaaaaagc acagctagat 32040caaaagaaat gcgattttca aggtgctcaa cggtggcttc cagcaaagcc tccacgcgca 32100catccaagaa caaaagaata ccaaaagaag gagcattttc taactcctca atcatcatat 32160tacattcctg caccattccc agataatttt cagctttcca gccttgaatt attcgtgtca 32220gttcttgtgg taaatccaat ccacacatta caaacaggtc ccggagggcg ccctccacca 32280ccattcttaa acacaccctc ataatgacaa aatatcttgc tcctgtgtca cctgtagcga 32340attgagaatg gcaacatcaa ttgacatgcc cttggctcta agttcttctt taagttctag 32400ttgtaaaaac tctctcatat tatcaccaaa ctgcttagcc agaagccccc cgggaacaag 32460agcaggggac gctacagtgc agtacaagcg cagacctccc caattggctc cagcaaaaac 32520aagattggaa taagcatatt gggaaccgcc agtaatatca tcgaagttgc tggaaatata 32580atcaggcaga gtttcttgta aaaattgaat aaaagaaaaa tttgccaaaa aaacattcaa 32640aacctctggg atgcaaatgc aataggttac cgcgctgcgc tccaacattg ttagttttga 32700attagtctgc aaaaataaaa aaaaaaacaa gcgtcatatc atagtagcct gacgaacaga 32760tggataaatc agtctttcca tcacaagaca agccacaggg tctccagctc gaccctcgta 32820aaacctgtca tcatgattaa acaacagcac cgaaagttcc tcgcggtgac cagcatgaat 32880aattcttgat gaagcataca atccagacat gttagcatca gttaacgaga aaaaacagcc 32940aacatagcct ttgggtataa ttatgcttaa tcgtaagtat agcaaagcca cccctcgcgg 33000atacaaagta aaaggcacag gagaataaaa aatataatta tttctctgct gctgttcagg 33060caacgtcgcc cccggtccct ctaaatacac atacaaagcc tcatcagcca tggcttacca 33120gacaaagtac agcgggcaca caaagcacaa gctctaaagt gactctccaa cctctccaca 33180atatatatat acacaagccc taaactgacg taatgggagt aaagtgtaaa aaatcccgcc 33240aaacccaaca cacaccccga aactgcgtca ccagggaaaa gtacagtttc acttccgcaa 33300tcccaacagg cgtaacttcc tctttctcac ggtacgtgat atcccactaa cttgcaacgt 33360cattttccca cggtcgcacc gcccctttta gccgttaacc ccacagccaa tcaccacacg 33420atccacactt tttaaaatca cctcatttac atattggcac cattccatct ataaggtata 33480ttatatagat aga 334931734119DNAArtificial SequenceNG-343 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes IFNa, and CD80, inserted in the region By. The transgene cassette contains a 5' SSA, IFNa cDNA sequence, P2A peptide, CD80 cDNA sequence and a 3' poly(A) 17tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt

tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt

acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc accatggcct tgacctttgc tttactggtg 29400gccctcctgg tgctcagctg caagtcaagc tgctctgtgg gctgtgatct gcctcaaacc 29460cacagcctgg gtagcaggag gaccttgatg ctcctggcac agatgaggag aatctctctt 29520ttctcctgct tgaaggacag acatgacttt ggatttcccc aggaggagtt tggcaaccag 29580ttccaaaagg ctgaaaccat ccctgtcctc catgagatga tccagcagat cttcaatctc 29640ttcagcacaa aggactcatc tgctgcttgg gatgagaccc tcctagacaa attctacact 29700gaactctacc agcagctgaa tgacctggaa gcctgtgtga tacagggggt gggggtgaca 29760gagactcccc tgatgaagga ggactccatt ctggctgtga ggaaatactt ccaaagaatc 29820actctctatc tgaaagagaa gaaatacagc ccttgtgcct gggaggttgt cagagcagaa 29880atcatgagat ctttttcttt gtcaacaaac ttgcaagaaa gtttaagaag taaggaagga 29940agcggagcta ctaacttcag cctgctgaag caggctggag acgtggagga gaaccctgga 30000cctggccaca cacggaggca gggaacatca ccatccaagt gtccatacct caatttcttt 30060cagctcttgg tgctggctgg tctttctcac ttctgttcag gtgttatcca cgtgaccaag 30120gaagtgaaag aagtggcaac gctgtcctgt ggtcacaatg tttctgttga agagctggca 30180caaactcgca tctactggca aaaggagaag aaaatggtgc tgactatgat gtctggggac 30240atgaatatat ggcccgagta caagaaccgg accatctttg atatcactaa taacctctcc 30300attgtgatcc tggctctgcg cccatctgac gagggcacat acgagtgtgt tgttctgaag 30360tatgaaaaag acgctttcaa gcgggaacac ctggctgaag tgacgttatc agtcaaagct 30420gacttcccta cacctagtat atctgacttt gaaattccaa cttctaatat tagaaggata 30480atttgctcaa cctctggagg ttttccagag cctcacctct cctggttgga aaatggagaa 30540gaattaaatg ccatcaacac aacagtttcc caagatcctg aaactgagct ctatgctgtt 30600agcagcaaac tggatttcaa tatgacaacc aaccacagct tcatgtgtct catcaagtat 30660ggacatttaa gagtgaatca gaccttcaac tggaatacaa ccaagcaaga gcattttcct 30720gataacctgc tcccatcctg ggccattacc ttaatctcag taaatggaat ttttgtgata 30780tgctgcctga cctactgctt tgccccaaga tgcagagaga gaaggaggaa tgagagattg 30840agaagggaaa gtgtacgccc tgtataagct agcttgactg actgagatac agcgtacctt 30900cagctcacag acatgataag atacattgat gagtttggac aaaccacaac tagaatgcag 30960tgaaaaaaat gctttatttg tgaaatttgt gatgctattg ctttatttgt aaccattata 31020agctgcaata aacaagttaa caacaacaat tgcattcatt ttatgtttca ggttcagggg 31080gaggtgtggg aggtttttta aagcaagtaa aacctctaca aatgtggtag tcgtcagcta 31140tcctgcagga acttgtttat ttgaaaatca attcacaaaa tccgagtagt tattttgcct 31200cccccttccc atttaacaga atacaccaat ctctccccac gcacagcttt aaacatttgg 31260ataccattag atatagacat ggttttagat tccacattcc aaacagtttc agagcgagcc 31320aatctggggt cagtgataga taaaaatcca tcgggatagt cttttaaagc gctttcacag 31380tccaactgct gcggatgcga ctccggagtc tggatcacgg tcatctggaa gaagaacgat 31440gggaatcata atccgaaaac ggtatcggac gattgtgtct catcaaaccc acaagcagcc 31500gctgtctgcg tcgctccgtg cgactgctgt ttatgggatc agggtccaca gtgtcctgaa 31560gcatgatttt aatagccctt aacatcaact ttctggtgcg atgcgcgcag caacgcattc 31620tgatttcact caaatctttg cagtaggtac aacacattat tacaatattg tttaataaac 31680cataattaaa agcgctccag ccaaaactca tatctgatat aatcgcccct gcatgaccat 31740cataccaaag tttaatataa attaaatgac gttccctcaa aaacacacta cccacataca 31800tgatctcttt tggcatgtgc atattaacaa tctgtctgta ccatggacaa cgttggttaa 31860tcatgcaacc caatataacc ttccggaacc

acactgccaa caccgctccc ccagccatgc 31920attgaagtga accctgctga ttacaatgac aatgaagaac ccaattctct cgaccgtgaa 31980tcacttgaga atgaaaaata tctatagtgg cacaacatag acataaatgc atgcatcttc 32040tcataatttt taactcctca ggatttagaa acatatccca gggaatagga agctcttgca 32100gaacagtaaa gctggcagaa caaggaagac cacgaacaca acttacacta tgcatagtca 32160tagtatcaca atctggcaac agcgggtggt cttcagtcat agaagctcgg gtttcatttt 32220cctcacaacg tggtaactgg gctctggtgt aagggtgatg tctggcgcat gatgtcgagc 32280gtgcgcgcaa ccttgtcata atggagttgc ttcctgacat tctcgtattt tgtatagcaa 32340aacgcggccc tggcagaaca cactcttctt cgccttctat cctgccgctt agcgtgttcc 32400gtgtgatagt tcaagtacaa ccacactctt aagttggtca aaagaatgct ggcttcagtt 32460gtaatcaaaa ctccatcgca tctaatcgtt ctgaggaaat catccaagca atgcaactgg 32520attgtgtttc aagcaggaga ggagagggaa gagacggaag aaccatgtta atttttattc 32580caaacgatct cgcagtactt caaattgtag atcgcgcaga tggcatctct cgcccccact 32640gtgttggtga aaaagcacag ctagatcaaa agaaatgcga ttttcaaggt gctcaacggt 32700ggcttccagc aaagcctcca cgcgcacatc caagaacaaa agaataccaa aagaaggagc 32760attttctaac tcctcaatca tcatattaca ttcctgcacc attcccagat aattttcagc 32820tttccagcct tgaattattc gtgtcagttc ttgtggtaaa tccaatccac acattacaaa 32880caggtcccgg agggcgccct ccaccaccat tcttaaacac accctcataa tgacaaaata 32940tcttgctcct gtgtcacctg tagcgaattg agaatggcaa catcaattga catgcccttg 33000gctctaagtt cttctttaag ttctagttgt aaaaactctc tcatattatc accaaactgc 33060ttagccagaa gccccccggg aacaagagca ggggacgcta cagtgcagta caagcgcaga 33120cctccccaat tggctccagc aaaaacaaga ttggaataag catattggga accgccagta 33180atatcatcga agttgctgga aatataatca ggcagagttt cttgtaaaaa ttgaataaaa 33240gaaaaatttg ccaaaaaaac attcaaaacc tctgggatgc aaatgcaata ggttaccgcg 33300ctgcgctcca acattgttag ttttgaatta gtctgcaaaa ataaaaaaaa aaacaagcgt 33360catatcatag tagcctgacg aacagatgga taaatcagtc tttccatcac aagacaagcc 33420acagggtctc cagctcgacc ctcgtaaaac ctgtcatcat gattaaacaa cagcaccgaa 33480agttcctcgc ggtgaccagc atgaataatt cttgatgaag catacaatcc agacatgtta 33540gcatcagtta acgagaaaaa acagccaaca tagcctttgg gtataattat gcttaatcgt 33600aagtatagca aagccacccc tcgcggatac aaagtaaaag gcacaggaga ataaaaaata 33660taattatttc tctgctgctg ttcaggcaac gtcgcccccg gtccctctaa atacacatac 33720aaagcctcat cagccatggc ttaccagaca aagtacagcg ggcacacaaa gcacaagctc 33780taaagtgact ctccaacctc tccacaatat atatatacac aagccctaaa ctgacgtaat 33840gggagtaaag tgtaaaaaat cccgccaaac ccaacacaca ccccgaaact gcgtcaccag 33900ggaaaagtac agtttcactt ccgcaatccc aacaggcgta acttcctctt tctcacggta 33960cgtgatatcc cactaacttg caacgtcatt ttcccacggt cgcaccgccc cttttagccg 34020ttaaccccac agccaatcac cacacgatcc acacttttta aaatcacctc atttacatat 34080tggcaccatt ccatctataa ggtatattat atagataga 341191834131DNAArtificial SequenceNG-345 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes Flt3 Ligand, MIP1a and IFNa, inserted in the region BY. The transgene cassette contains a 5' SSA, Flt3 Ligand cDNA , P2A peptide sequence, MIP1a cDNA sequence 18tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct

12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct

27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc accatgacag tgctggcgcc agcctggagc 29400ccaacaacct atctcctcct gctgctgctg ctgagctcgg gactcagtgg gacccaggac 29460tgctccttcc aacacagccc catctcctcc gacttcgctg tcaaaatccg tgagctgtct 29520gactacctgc ttcaagatta cccagtcacc gtggcctcca acctccagga cgaggagctc 29580tgcgggggcc tctggcggct ggtcctggca cagcgctgga tggagcggct caagactgtc 29640gctgggtcca agatgcaagg cttgctggag cgcgtgaaca cggagataca ctttgtcacc 29700aaatgtgcct ttcagccccc ccccagctgt cttcgcttcg tccagaccaa catctcccgc 29760ctcctacagg agacctccga gcagctggtg gcgctgaagc cctggatcac tcgccagaac 29820ttctcccggt gcctggagct gcagtgtcag cccgactcct caaccctgcc acccccatgg 29880agtccccggc ccctggaggc cacagccccg ggaagcggag ctactaactt cagcctgctg 29940aagcaggctg gagacgtgga ggagaaccct ggacctcagg tctccactgc tgcccttgcc 30000gtcctcctct gcaccatggc tctctgcaac caggtcctct ctgcaccact tgctgctgac 30060acgccgaccg cctgctgctt cagctacacc tcccgacaga ttccacagaa tttcatagct 30120gactactttg agacgagcag ccagtgctcc aagcccagtg tcatcttcct aaccaagaga 30180ggccggcagg tctgtgctga ccccagtgag gagtgggtcc agaaatacgt cagtgacctg 30240gagctgagtg ccggaagcgg agagggcaga ggaagtctgc taacatgcgg tgacgtcgag 30300gagaatcctg gacctgcctt gacctttgct ttactggtgg ccctcctggt gctcagctgc 30360aagtcaagct gctctgtggg ctgtgatctg cctcaaaccc acagcctggg tagcaggagg 30420accttgatgc tcctggcaca gatgaggaga atctctcttt tctcctgctt gaaggacaga 30480catgactttg gatttcccca ggaggagttt ggcaaccagt tccaaaaggc tgaaaccatc 30540cctgtcctcc atgagatgat ccagcagatc ttcaatctct tcagcacaaa ggactcatct 30600gctgcttggg atgagaccct cctagacaaa ttctacactg aactctacca gcagctgaat 30660gacctggaag cctgtgtgat acagggggtg ggggtgacag agactcccct gatgaaggag 30720gactccattc tggctgtgag gaaatacttc caaagaatca ctctctatct gaaagagaag 30780aaatacagcc cttgtgcctg ggaggttgtc agagcagaaa tcatgagatc tttttctttg 30840tcaacaaact tgcaagaaag tttaagaagt aaggaataag ctagcttgac tgactgagat 30900acagcgtacc ttcagctcac agacatgata agatacattg atgagtttgg acaaaccaca 30960actagaatgc agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt 31020gtaaccatta taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt 31080caggttcagg gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt 31140agtcgtcagc tatcctgcag gaacttgttt atttgaaaat caattcacaa aatccgagta 31200gttattttgc ctcccccttc ccatttaaca gaatacacca atctctcccc acgcacagct 31260ttaaacattt ggataccatt agatatagac atggttttag attccacatt ccaaacagtt 31320tcagagcgag ccaatctggg gtcagtgata gataaaaatc catcgggata gtcttttaaa 31380gcgctttcac agtccaactg ctgcggatgc gactccggag tctggatcac ggtcatctgg 31440aagaagaacg atgggaatca taatccgaaa acggtatcgg acgattgtgt ctcatcaaac 31500ccacaagcag ccgctgtctg cgtcgctccg tgcgactgct gtttatggga tcagggtcca 31560cagtgtcctg aagcatgatt ttaatagccc ttaacatcaa ctttctggtg cgatgcgcgc 31620agcaacgcat tctgatttca ctcaaatctt tgcagtaggt acaacacatt attacaatat 31680tgtttaataa accataatta aaagcgctcc agccaaaact catatctgat ataatcgccc 31740ctgcatgacc atcataccaa agtttaatat aaattaaatg acgttccctc aaaaacacac 31800tacccacata catgatctct tttggcatgt gcatattaac aatctgtctg taccatggac 31860aacgttggtt aatcatgcaa cccaatataa ccttccggaa ccacactgcc aacaccgctc 31920ccccagccat gcattgaagt gaaccctgct gattacaatg acaatgaaga acccaattct 31980ctcgaccgtg aatcacttga gaatgaaaaa tatctatagt ggcacaacat agacataaat 32040gcatgcatct tctcataatt tttaactcct caggatttag aaacatatcc cagggaatag 32100gaagctcttg cagaacagta aagctggcag aacaaggaag accacgaaca caacttacac 32160tatgcatagt catagtatca caatctggca acagcgggtg gtcttcagtc atagaagctc 32220gggtttcatt ttcctcacaa cgtggtaact gggctctggt gtaagggtga tgtctggcgc 32280atgatgtcga gcgtgcgcgc aaccttgtca taatggagtt gcttcctgac attctcgtat 32340tttgtatagc aaaacgcggc cctggcagaa cacactcttc ttcgccttct atcctgccgc 32400ttagcgtgtt ccgtgtgata gttcaagtac aaccacactc ttaagttggt caaaagaatg 32460ctggcttcag ttgtaatcaa aactccatcg catctaatcg ttctgaggaa atcatccaag 32520caatgcaact ggattgtgtt tcaagcagga gaggagaggg aagagacgga agaaccatgt 32580taatttttat tccaaacgat ctcgcagtac ttcaaattgt agatcgcgca gatggcatct 32640ctcgccccca ctgtgttggt gaaaaagcac agctagatca aaagaaatgc gattttcaag 32700gtgctcaacg gtggcttcca gcaaagcctc cacgcgcaca tccaagaaca aaagaatacc 32760aaaagaagga gcattttcta actcctcaat catcatatta cattcctgca ccattcccag 32820ataattttca gctttccagc cttgaattat tcgtgtcagt tcttgtggta aatccaatcc 32880acacattaca aacaggtccc ggagggcgcc ctccaccacc attcttaaac acaccctcat 32940aatgacaaaa tatcttgctc ctgtgtcacc tgtagcgaat tgagaatggc aacatcaatt 33000gacatgccct tggctctaag ttcttcttta agttctagtt gtaaaaactc tctcatatta 33060tcaccaaact gcttagccag aagccccccg ggaacaagag caggggacgc tacagtgcag 33120tacaagcgca gacctcccca attggctcca gcaaaaacaa gattggaata agcatattgg 33180gaaccgccag taatatcatc gaagttgctg gaaatataat caggcagagt ttcttgtaaa 33240aattgaataa aagaaaaatt tgccaaaaaa acattcaaaa cctctgggat gcaaatgcaa 33300taggttaccg cgctgcgctc caacattgtt agttttgaat tagtctgcaa aaataaaaaa 33360aaaaacaagc gtcatatcat agtagcctga cgaacagatg gataaatcag tctttccatc 33420acaagacaag ccacagggtc tccagctcga ccctcgtaaa acctgtcatc atgattaaac 33480aacagcaccg aaagttcctc gcggtgacca gcatgaataa ttcttgatga agcatacaat 33540ccagacatgt tagcatcagt taacgagaaa aaacagccaa catagccttt gggtataatt 33600atgcttaatc gtaagtatag caaagccacc cctcgcggat acaaagtaaa aggcacagga 33660gaataaaaaa tataattatt tctctgctgc tgttcaggca acgtcgcccc cggtccctct 33720aaatacacat acaaagcctc atcagccatg gcttaccaga caaagtacag cgggcacaca 33780aagcacaagc tctaaagtga ctctccaacc tctccacaat atatatatac acaagcccta 33840aactgacgta atgggagtaa agtgtaaaaa atcccgccaa acccaacaca caccccgaaa 33900ctgcgtcacc agggaaaagt acagtttcac ttccgcaatc ccaacaggcg taacttcctc 33960tttctcacgg tacgtgatat cccactaact tgcaacgtca ttttcccacg gtcgcaccgc 34020cccttttagc cgttaacccc acagccaatc accacacgat ccacactttt taaaatcacc 34080tcatttacat attggcacca ttccatctat aaggtatatt atatagatag a 341311934432DNAArtificial SequenceNG-346 virus genome sequence comprising a transgene cassette that encodes Flt3 Ligand, MIP1a and CD80, employing SSA and P2A sequence, inserted in the region BY 19tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg

gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct

cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc accatgacag tgctggcgcc agcctggagc 29400ccaacaacct atctcctcct gctgctgctg ctgagctcgg gactcagtgg gacccaggac 29460tgctccttcc aacacagccc catctcctcc gacttcgctg tcaaaatccg tgagctgtct 29520gactacctgc ttcaagatta cccagtcacc gtggcctcca acctccagga cgaggagctc 29580tgcgggggcc tctggcggct ggtcctggca cagcgctgga tggagcggct caagactgtc 29640gctgggtcca agatgcaagg cttgctggag cgcgtgaaca cggagataca ctttgtcacc 29700aaatgtgcct ttcagccccc ccccagctgt cttcgcttcg tccagaccaa catctcccgc 29760ctcctacagg agacctccga gcagctggtg gcgctgaagc cctggatcac tcgccagaac 29820ttctcccggt gcctggagct gcagtgtcag cccgactcct caaccctgcc acccccatgg 29880agtccccggc ccctggaggc cacagccccg ggaagcggag ctactaactt cagcctgctg 29940aagcaggctg gagacgtgga ggagaaccct ggacctcagg tctccactgc tgcccttgcc 30000gtcctcctct gcaccatggc tctctgcaac caggtcctct ctgcaccact tgctgctgac 30060acgccgaccg cctgctgctt cagctacacc tcccgacaga ttccacagaa tttcatagct 30120gactactttg agacgagcag ccagtgctcc aagcccagtg tcatcttcct aaccaagaga 30180ggccggcagg tctgtgctga ccccagtgag gagtgggtcc agaaatacgt cagtgacctg 30240gagctgagtg ccggaagcgg agagggcaga ggaagtctgc taacatgcgg tgacgtcgag 30300gagaatcctg gacctggcca cacacggagg cagggaacat caccatccaa gtgtccatac 30360ctcaatttct ttcagctctt ggtgctggct ggtctttctc acttctgttc aggtgttatc 30420cacgtgacca aggaagtgaa agaagtggca acgctgtcct gtggtcacaa tgtttctgtt 30480gaagagctgg cacaaactcg catctactgg caaaaggaga agaaaatggt gctgactatg 30540atgtctgggg acatgaatat atggcccgag tacaagaacc ggaccatctt tgatatcact 30600aataacctct ccattgtgat cctggctctg cgcccatctg acgagggcac atacgagtgt 30660gttgttctga agtatgaaaa agacgctttc aagcgggaac acctggctga agtgacgtta 30720tcagtcaaag ctgacttccc tacacctagt atatctgact ttgaaattcc aacttctaat 30780attagaagga taatttgctc aacctctgga ggttttccag agcctcacct ctcctggttg 30840gaaaatggag aagaattaaa tgccatcaac acaacagttt cccaagatcc tgaaactgag 30900ctctatgctg ttagcagcaa actggatttc aatatgacaa ccaaccacag cttcatgtgt 30960ctcatcaagt atggacattt aagagtgaat cagaccttca actggaatac aaccaagcaa 31020gagcattttc ctgataacct gctcccatcc tgggccatta ccttaatctc agtaaatgga 31080atttttgtga tatgctgcct gacctactgc tttgccccaa gatgcagaga gagaaggagg 31140aatgagagat tgagaaggga aagtgtacgc cctgtataag ctagcttgac tgactgagat 31200acagcgtacc ttcagctcac agacatgata agatacattg atgagtttgg acaaaccaca 31260actagaatgc agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt 31320gtaaccatta taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt 31380caggttcagg gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt 31440agtcgtcagc tatcctgcag gaacttgttt atttgaaaat caattcacaa aatccgagta 31500gttattttgc ctcccccttc ccatttaaca gaatacacca atctctcccc acgcacagct 31560ttaaacattt ggataccatt agatatagac atggttttag attccacatt ccaaacagtt 31620tcagagcgag ccaatctggg gtcagtgata gataaaaatc catcgggata gtcttttaaa 31680gcgctttcac agtccaactg ctgcggatgc gactccggag tctggatcac ggtcatctgg 31740aagaagaacg atgggaatca taatccgaaa acggtatcgg acgattgtgt ctcatcaaac 31800ccacaagcag ccgctgtctg cgtcgctccg tgcgactgct gtttatggga tcagggtcca 31860cagtgtcctg aagcatgatt ttaatagccc ttaacatcaa ctttctggtg cgatgcgcgc 31920agcaacgcat tctgatttca ctcaaatctt tgcagtaggt acaacacatt attacaatat 31980tgtttaataa accataatta aaagcgctcc agccaaaact catatctgat ataatcgccc 32040ctgcatgacc atcataccaa agtttaatat aaattaaatg acgttccctc aaaaacacac 32100tacccacata catgatctct tttggcatgt gcatattaac aatctgtctg taccatggac 32160aacgttggtt aatcatgcaa cccaatataa ccttccggaa ccacactgcc aacaccgctc 32220ccccagccat gcattgaagt gaaccctgct gattacaatg acaatgaaga acccaattct 32280ctcgaccgtg aatcacttga gaatgaaaaa tatctatagt ggcacaacat agacataaat 32340gcatgcatct tctcataatt tttaactcct caggatttag aaacatatcc cagggaatag 32400gaagctcttg cagaacagta aagctggcag aacaaggaag accacgaaca caacttacac 32460tatgcatagt catagtatca caatctggca acagcgggtg gtcttcagtc atagaagctc 32520gggtttcatt ttcctcacaa cgtggtaact gggctctggt gtaagggtga tgtctggcgc 32580atgatgtcga gcgtgcgcgc aaccttgtca taatggagtt gcttcctgac attctcgtat 32640tttgtatagc aaaacgcggc cctggcagaa cacactcttc ttcgccttct atcctgccgc 32700ttagcgtgtt ccgtgtgata gttcaagtac aaccacactc ttaagttggt caaaagaatg 32760ctggcttcag ttgtaatcaa aactccatcg catctaatcg ttctgaggaa atcatccaag 32820caatgcaact ggattgtgtt tcaagcagga gaggagaggg aagagacgga agaaccatgt 32880taatttttat tccaaacgat ctcgcagtac ttcaaattgt agatcgcgca gatggcatct 32940ctcgccccca ctgtgttggt gaaaaagcac agctagatca aaagaaatgc gattttcaag 33000gtgctcaacg gtggcttcca gcaaagcctc cacgcgcaca tccaagaaca aaagaatacc 33060aaaagaagga gcattttcta actcctcaat catcatatta cattcctgca ccattcccag 33120ataattttca gctttccagc cttgaattat tcgtgtcagt tcttgtggta aatccaatcc 33180acacattaca aacaggtccc ggagggcgcc ctccaccacc attcttaaac acaccctcat 33240aatgacaaaa tatcttgctc ctgtgtcacc tgtagcgaat tgagaatggc aacatcaatt 33300gacatgccct tggctctaag ttcttcttta agttctagtt gtaaaaactc tctcatatta 33360tcaccaaact gcttagccag aagccccccg ggaacaagag caggggacgc tacagtgcag 33420tacaagcgca gacctcccca attggctcca gcaaaaacaa gattggaata agcatattgg 33480gaaccgccag taatatcatc gaagttgctg gaaatataat caggcagagt ttcttgtaaa 33540aattgaataa aagaaaaatt tgccaaaaaa acattcaaaa cctctgggat gcaaatgcaa 33600taggttaccg cgctgcgctc caacattgtt agttttgaat tagtctgcaa aaataaaaaa 33660aaaaacaagc gtcatatcat agtagcctga cgaacagatg gataaatcag tctttccatc 33720acaagacaag ccacagggtc tccagctcga ccctcgtaaa acctgtcatc atgattaaac 33780aacagcaccg aaagttcctc gcggtgacca gcatgaataa ttcttgatga agcatacaat 33840ccagacatgt tagcatcagt taacgagaaa aaacagccaa catagccttt gggtataatt 33900atgcttaatc gtaagtatag caaagccacc cctcgcggat acaaagtaaa aggcacagga 33960gaataaaaaa tataattatt tctctgctgc tgttcaggca acgtcgcccc cggtccctct 34020aaatacacat acaaagcctc atcagccatg gcttaccaga caaagtacag cgggcacaca 34080aagcacaagc tctaaagtga ctctccaacc tctccacaat atatatatac acaagcccta 34140aactgacgta atgggagtaa agtgtaaaaa atcccgccaa acccaacaca caccccgaaa 34200ctgcgtcacc agggaaaagt acagtttcac ttccgcaatc ccaacaggcg taacttcctc 34260tttctcacgg tacgtgatat cccactaact tgcaacgtca ttttcccacg gtcgcaccgc 34320cccttttagc cgttaacccc acagccaatc accacacgat ccacactttt taaaatcacc 34380tcatttacat attggcacca ttccatctat aaggtatatt atatagatag ga 344322034458DNAArtificial SequenceNG-347 virus genome sequence comprising a transgene cassette encoding IFNa, MIP1a and CD80, employing SSA and a P2A sequence, inserted in the region BY 20tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg

agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct

ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc accatggcct tgacctttgc tttactggtg 29400gccctcctgg tgctcagctg caagtcaagc tgctctgtgg gctgtgatct gcctcaaacc 29460cacagcctgg gtagcaggag gaccttgatg ctcctggcac agatgaggag aatctctctt 29520ttctcctgct tgaaggacag acatgacttt ggatttcccc aggaggagtt tggcaaccag 29580ttccaaaagg ctgaaaccat ccctgtcctc catgagatga tccagcagat cttcaatctc 29640ttcagcacaa aggactcatc tgctgcttgg gatgagaccc tcctagacaa attctacact 29700gaactctacc agcagctgaa tgacctggaa gcctgtgtga tacagggggt gggggtgaca 29760gagactcccc tgatgaagga ggactccatt ctggctgtga ggaaatactt ccaaagaatc 29820actctctatc tgaaagagaa gaaatacagc ccttgtgcct gggaggttgt cagagcagaa 29880atcatgagat ctttttcttt gtcaacaaac ttgcaagaaa gtttaagaag taaggaagga 29940agcggagcta ctaacttcag cctgctgaag caggctggag acgtggagga gaaccctgga 30000cctcaggtct ccactgctgc ccttgccgtc ctcctctgca ccatggctct ctgcaaccag 30060gtcctctctg caccacttgc tgctgacacg ccgaccgcct gctgcttcag ctacacctcc 30120cgacagattc cacagaattt catagctgac tactttgaga cgagcagcca gtgctccaag 30180cccagtgtca tcttcctaac caagagaggc cggcaggtct gtgctgaccc cagtgaggag 30240tgggtccaga aatacgtcag tgacctggag ctgagtgccg gaagcggaga gggcagagga 30300agtctgctaa catgcggtga cgtcgaggag aatcctggac ctggccacac acggaggcag 30360ggaacatcac catccaagtg tccatacctc aatttctttc agctcttggt gctggctggt 30420ctttctcact tctgttcagg tgttatccac gtgaccaagg aagtgaaaga agtggcaacg 30480ctgtcctgtg gtcacaatgt ttctgttgaa gagctggcac aaactcgcat ctactggcaa 30540aaggagaaga aaatggtgct gactatgatg tctggggaca tgaatatatg gcccgagtac 30600aagaaccgga ccatctttga tatcactaat aacctctcca ttgtgatcct ggctctgcgc 30660ccatctgacg agggcacata cgagtgtgtt gttctgaagt atgaaaaaga cgctttcaag 30720cgggaacacc tggctgaagt gacgttatca gtcaaagctg acttccctac acctagtata 30780tctgactttg aaattccaac ttctaatatt agaaggataa tttgctcaac ctctggaggt 30840tttccagagc ctcacctctc ctggttggaa aatggagaag aattaaatgc catcaacaca 30900acagtttccc aagatcctga aactgagctc tatgctgtta gcagcaaact ggatttcaat 30960atgacaacca accacagctt catgtgtctc atcaagtatg gacatttaag agtgaatcag 31020accttcaact ggaatacaac caagcaagag cattttcctg ataacctgct cccatcctgg 31080gccattacct taatctcagt aaatggaatt tttgtgatat gctgcctgac ctactgcttt 31140gccccaagat gcagagagag aaggaggaat gagagattga gaagggaaag tgtacgccct 31200gtataagcta gcttgactga ctgagataca gcgtaccttc agctcacaga catgataaga 31260tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg ctttatttgt 31320gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa acaagttaac 31380aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga ggttttttaa 31440agcaagtaaa acctctacaa atgtggtagt cgtcagctat cctgcaggaa cttgtttatt 31500tgaaaatcaa ttcacaaaat ccgagtagtt attttgcctc ccccttccca tttaacagaa 31560tacaccaatc tctccccacg cacagcttta aacatttgga taccattaga tatagacatg 31620gttttagatt ccacattcca aacagtttca gagcgagcca atctggggtc agtgatagat 31680aaaaatccat cgggatagtc ttttaaagcg ctttcacagt ccaactgctg cggatgcgac 31740tccggagtct ggatcacggt catctggaag aagaacgatg ggaatcataa tccgaaaacg 31800gtatcggacg attgtgtctc atcaaaccca caagcagccg ctgtctgcgt cgctccgtgc 31860gactgctgtt tatgggatca gggtccacag tgtcctgaag catgatttta atagccctta 31920acatcaactt tctggtgcga tgcgcgcagc aacgcattct gatttcactc aaatctttgc 31980agtaggtaca acacattatt acaatattgt ttaataaacc ataattaaaa gcgctccagc 32040caaaactcat atctgatata atcgcccctg catgaccatc ataccaaagt ttaatataaa 32100ttaaatgacg ttccctcaaa aacacactac ccacatacat gatctctttt ggcatgtgca 32160tattaacaat ctgtctgtac catggacaac gttggttaat catgcaaccc aatataacct 32220tccggaacca cactgccaac accgctcccc cagccatgca ttgaagtgaa ccctgctgat 32280tacaatgaca atgaagaacc caattctctc gaccgtgaat cacttgagaa tgaaaaatat 32340ctatagtggc acaacataga cataaatgca tgcatcttct cataattttt aactcctcag 32400gatttagaaa catatcccag ggaataggaa gctcttgcag aacagtaaag ctggcagaac 32460aaggaagacc acgaacacaa cttacactat gcatagtcat agtatcacaa tctggcaaca 32520gcgggtggtc ttcagtcata gaagctcggg tttcattttc ctcacaacgt ggtaactggg 32580ctctggtgta agggtgatgt ctggcgcatg atgtcgagcg tgcgcgcaac cttgtcataa 32640tggagttgct tcctgacatt ctcgtatttt gtatagcaaa acgcggccct ggcagaacac 32700actcttcttc gccttctatc ctgccgctta gcgtgttccg tgtgatagtt caagtacaac 32760cacactctta agttggtcaa aagaatgctg gcttcagttg taatcaaaac tccatcgcat 32820ctaatcgttc tgaggaaatc atccaagcaa tgcaactgga ttgtgtttca agcaggagag 32880gagagggaag agacggaaga accatgttaa tttttattcc aaacgatctc gcagtacttc 32940aaattgtaga tcgcgcagat ggcatctctc gcccccactg tgttggtgaa aaagcacagc 33000tagatcaaaa gaaatgcgat tttcaaggtg ctcaacggtg gcttccagca aagcctccac 33060gcgcacatcc aagaacaaaa gaataccaaa agaaggagca ttttctaact cctcaatcat 33120catattacat tcctgcacca ttcccagata attttcagct ttccagcctt gaattattcg 33180tgtcagttct tgtggtaaat ccaatccaca cattacaaac aggtcccgga gggcgccctc 33240caccaccatt cttaaacaca ccctcataat gacaaaatat cttgctcctg tgtcacctgt 33300agcgaattga gaatggcaac atcaattgac atgcccttgg ctctaagttc ttctttaagt 33360tctagttgta aaaactctct catattatca ccaaactgct tagccagaag ccccccggga 33420acaagagcag gggacgctac agtgcagtac aagcgcagac ctccccaatt ggctccagca 33480aaaacaagat tggaataagc atattgggaa ccgccagtaa tatcatcgaa gttgctggaa 33540atataatcag gcagagtttc ttgtaaaaat tgaataaaag aaaaatttgc caaaaaaaca 33600ttcaaaacct ctgggatgca aatgcaatag gttaccgcgc tgcgctccaa cattgttagt 33660tttgaattag tctgcaaaaa taaaaaaaaa aacaagcgtc atatcatagt agcctgacga 33720acagatggat aaatcagtct ttccatcaca agacaagcca cagggtctcc agctcgaccc 33780tcgtaaaacc tgtcatcatg attaaacaac agcaccgaaa gttcctcgcg gtgaccagca 33840tgaataattc ttgatgaagc atacaatcca gacatgttag catcagttaa cgagaaaaaa 33900cagccaacat agcctttggg tataattatg cttaatcgta agtatagcaa agccacccct 33960cgcggataca aagtaaaagg

cacaggagaa taaaaaatat aattatttct ctgctgctgt 34020tcaggcaacg tcgcccccgg tccctctaaa tacacataca aagcctcatc agccatggct 34080taccagacaa agtacagcgg gcacacaaag cacaagctct aaagtgactc tccaacctct 34140ccacaatata tatatacaca agccctaaac tgacgtaatg ggagtaaagt gtaaaaaatc 34200ccgccaaacc caacacacac cccgaaactg cgtcaccagg gaaaagtaca gtttcacttc 34260cgcaatccca acaggcgtaa cttcctcttt ctcacggtac gtgatatccc actaacttgc 34320aacgtcattt tcccacggtc gcaccgcccc ttttagccgt taaccccaca gccaatcacc 34380acacgatcca cactttttaa aatcacctca tttacatatt ggcaccattc catctataag 34440gtatattata tagataga 344582132326DNAArtificial SequenceEnAd Genome 21tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa

aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttaact tgtttatttg aaaatcaatt cacaaaatcc gagtagttat 29400tttgcctccc ccttcccatt taacagaata caccaatctc tccccacgca cagctttaaa 29460catttggata ccattagata tagacatggt tttagattcc acattccaaa cagtttcaga 29520gcgagccaat ctggggtcag tgatagataa aaatccatcg

ggatagtctt ttaaagcgct 29580ttcacagtcc aactgctgcg gatgcgactc cggagtctgg atcacggtca tctggaagaa 29640gaacgatggg aatcataatc cgaaaacggt atcggacgat tgtgtctcat caaacccaca 29700agcagccgct gtctgcgtcg ctccgtgcga ctgctgttta tgggatcagg gtccacagtg 29760tcctgaagca tgattttaat agcccttaac atcaactttc tggtgcgatg cgcgcagcaa 29820cgcattctga tttcactcaa atctttgcag taggtacaac acattattac aatattgttt 29880aataaaccat aattaaaagc gctccagcca aaactcatat ctgatataat cgcccctgca 29940tgaccatcat accaaagttt aatataaatt aaatgacgtt ccctcaaaaa cacactaccc 30000acatacatga tctcttttgg catgtgcata ttaacaatct gtctgtacca tggacaacgt 30060tggttaatca tgcaacccaa tataaccttc cggaaccaca ctgccaacac cgctccccca 30120gccatgcatt gaagtgaacc ctgctgatta caatgacaat gaagaaccca attctctcga 30180ccgtgaatca cttgagaatg aaaaatatct atagtggcac aacatagaca taaatgcatg 30240catcttctca taatttttaa ctcctcagga tttagaaaca tatcccaggg aataggaagc 30300tcttgcagaa cagtaaagct ggcagaacaa ggaagaccac gaacacaact tacactatgc 30360atagtcatag tatcacaatc tggcaacagc gggtggtctt cagtcataga agctcgggtt 30420tcattttcct cacaacgtgg taactgggct ctggtgtaag ggtgatgtct ggcgcatgat 30480gtcgagcgtg cgcgcaacct tgtcataatg gagttgcttc ctgacattct cgtattttgt 30540atagcaaaac gcggccctgg cagaacacac tcttcttcgc cttctatcct gccgcttagc 30600gtgttccgtg tgatagttca agtacaacca cactcttaag ttggtcaaaa gaatgctggc 30660ttcagttgta atcaaaactc catcgcatct aatcgttctg aggaaatcat ccaagcaatg 30720caactggatt gtgtttcaag caggagagga gagggaagag acggaagaac catgttaatt 30780tttattccaa acgatctcgc agtacttcaa attgtagatc gcgcagatgg catctctcgc 30840ccccactgtg ttggtgaaaa agcacagcta gatcaaaaga aatgcgattt tcaaggtgct 30900caacggtggc ttccagcaaa gcctccacgc gcacatccaa gaacaaaaga ataccaaaag 30960aaggagcatt ttctaactcc tcaatcatca tattacattc ctgcaccatt cccagataat 31020tttcagcttt ccagccttga attattcgtg tcagttcttg tggtaaatcc aatccacaca 31080ttacaaacag gtcccggagg gcgccctcca ccaccattct taaacacacc ctcataatga 31140caaaatatct tgctcctgtg tcacctgtag cgaattgaga atggcaacat caattgacat 31200gcccttggct ctaagttctt ctttaagttc tagttgtaaa aactctctca tattatcacc 31260aaactgctta gccagaagcc ccccgggaac aagagcaggg gacgctacag tgcagtacaa 31320gcgcagacct ccccaattgg ctccagcaaa aacaagattg gaataagcat attgggaacc 31380gccagtaata tcatcgaagt tgctggaaat ataatcaggc agagtttctt gtaaaaattg 31440aataaaagaa aaatttgcca aaaaaacatt caaaacctct gggatgcaaa tgcaataggt 31500taccgcgctg cgctccaaca ttgttagttt tgaattagtc tgcaaaaata aaaaaaaaaa 31560caagcgtcat atcatagtag cctgacgaac agatggataa atcagtcttt ccatcacaag 31620acaagccaca gggtctccag ctcgaccctc gtaaaacctg tcatcatgat taaacaacag 31680caccgaaagt tcctcgcggt gaccagcatg aataattctt gatgaagcat acaatccaga 31740catgttagca tcagttaacg agaaaaaaca gccaacatag cctttgggta taattatgct 31800taatcgtaag tatagcaaag ccacccctcg cggatacaaa gtaaaaggca caggagaata 31860aaaaatataa ttatttctct gctgctgttc aggcaacgtc gcccccggtc cctctaaata 31920cacatacaaa gcctcatcag ccatggctta ccagacaaag tacagcgggc acacaaagca 31980caagctctaa agtgactctc caacctctcc acaatatata tatacacaag ccctaaactg 32040acgtaatggg agtaaagtgt aaaaaatccc gccaaaccca acacacaccc cgaaactgcg 32100tcaccaggga aaagtacagt ttcacttccg caatcccaac aggcgtaact tcctctttct 32160cacggtacgt gatatcccac taacttgcaa cgtcattttc ccacggtcgc accgcccctt 32220ttagccgtta accccacagc caatcaccac acgatccaca ctttttaaaa tcacctcatt 32280tacatattgg caccattcca tctataaggt atattatata gataga 32326225288DNAArtificial SequenceDNA SEQUENCE CORRESPONDING TO E2B REGION OF THE ENAD GENOME (BP 10355-5068) 22ctatggcatc tcgatccagc agacctcctc gtttcgcggg tttggacggc tcctggaata 60gggtatgaga cgatgggcgt ccagcgctgc cagggttcgg tccttccagg gtctcagtgt 120tcgagtcagg gttgtttccg tcacagtgaa ggggtgtgcg cctgcttggg cgcttgccag 180ggtgcgcttc agactcatcc tgctggtcga aaacttctgt cgcttggcgc cctgtatgtc 240ggccaagtag cagtttacca tgagttcgta gttgagcgcc tcggctgcgt ggcctttggc 300gcggagctta cctttggaag ttttcttgca taccgggcag tataggcatt tcagcgcata 360caacttgggc gcaaggaaaa cggattctgg ggagtatgca tctgcgccgc aggaggcgca 420aacagtttca cattccacca gccaggttaa atccggttca ttggggtcaa aaacaagttt 480tccgccatat tttttgatgc gtttcttacc tttggtctcc atgagttcgt gtcctcgttg 540agtgacaaac aggctgtccg tgtccccgta gactgatttt acaggcctct tctccagtgg 600agtgcctcgg tcttcttcgt acaggaactc tgaccactct gatacaaagg cgcgcgtcca 660ggccagcaca aaggaggcta tgtgggaggg gtagcgatcg ttgtcaacca gggggtccac 720cttttccaaa gtatgcaaac acatgtcacc ctcttcaaca tccaggaatg tgattggctt 780gtaggtgtat ttcacgtgac ctggggtccc cgctgggggg gtataaaagg gggcggttct 840ttgctcttcc tcactgtctt ccggatcgct gtccaggaac gtcagctgtt ggggtaggta 900ttccctctcg aaggcgggca tgacctctgc actcaggttg tcagtttcta agaacgagga 960ggatttgata ttgacagtgc cggttgagat gcctttcatg aggttttcgt ccatctggtc 1020agaaaacaca atttttttat tgtcaagttt ggtggcaaat gatccataca gggcgttgga 1080taaaagtttg gcaatggatc gcatggtttg gttcttttcc ttgtccgcgc gctctttggc 1140ggcgatgttg agttggacat actcgcgtgc caggcacttc cattcgggga agatagttgt 1200taattcatct ggcacgattc tcacttgcca ccctcgatta tgcaaggtaa ttaaatccac 1260actggtggcc acctcgcctc gaaggggttc attggtccaa cagagcctac ctcctttcct 1320agaacagaaa gggggaagtg ggtctagcat aagttcatcg ggagggtctg catccatggt 1380aaagattccc ggaagtaaat ccttatcaaa atagctgatg ggagtggggt catctaaggc 1440catttgccat tctcgagctg ccagtgcgcg ctcatatggg ttaaggggac tgccccatgg 1500catgggatgg gtgagtgcag aggcatacat gccacagatg tcatagacgt agatgggatc 1560ctcaaagatg cctatgtagg ttggatagca tcgcccccct ctgatacttg ctcgcacata 1620gtcatatagt tcatgtgatg gcgctagcag ccccggaccc aagttggtgc gattgggttt 1680ttctgttctg tagacgatct ggcgaaagat ggcgtgagaa ttggaagaga tggtgggtct 1740ttgaaaaatg ttgaaatggg catgaggtag acctacagag tctctgacaa agtgggcata 1800agattcttga agcttggtta ccagttcggc ggtgacaagt acgtctaggg cgcagtagtc 1860aagtgtttct tgaatgatgt cataacctgg ttggtttttc ttttcccaca gttcgcggtt 1920gagaaggtat tcttcgcgat ccttccagta ctcttctagc ggaaacccgt ctttgtctgc 1980acggtaagat cctagcatgt agaactgatt aactgccttg taagggcagc agcccttctc 2040tacgggtaga gagtatgctt gagcagcttt tcgtagcgaa gcgtgagtaa gggcaaaggt 2100gtctctgacc atgactttga ggaattggta tttgaagtcg atgtcgtcac aggctccctg 2160ttcccagagt tggaagtcta cccgtttctt gtaggcgggg ttgggcaaag cgaaagtaac 2220atcattgaag agaatcttgc cggccctggg catgaaattg cgagtgatgc gaaaaggctg 2280tggtacttcc gctcggttat tgataacctg ggcagctagg acgatctcgt cgaaaccgtt 2340gatgttgtgt cctacgatgt ataattctat gaaacgcggc gtgcctctga cgtgaggtag 2400cttactgagc tcatcaaagg ttaggtctgt ggggtcagat aaggcgtagt gttcgagagc 2460ccattcgtgc aggtgaggat tcgctttaag gaaggaggac cagaggtcca ctgccagtgc 2520tgtttgtaac tggtcccggt actgacgaaa atgccgtccg actgccattt tttctggggt 2580gacgcaatag aaggtttggg ggtcctgccg ccagcgatcc cacttgagtt ttatggcgag 2640gtcataggcg atgttgacga gccgctggtc tccagagagt ttcatgacca gcatgaaggg 2700gattagctgc ttgccaaagg accccatcca ggtgtaggtt tccacatcgt aggtgagaaa 2760gagcctttct gtgcgaggat gagagccaat cgggaagaac tggatctcct gccaccagtt 2820ggaggaatgg ctgttgatgt gatggaagta gaactccctg cgacgcgccg agcattcatg 2880cttgtgcttg tacagacggc cgcagtagtc gcagcgttgc acgggttgta tctcgtgaat 2940gagttgtacc tggcttccct tgacgagaaa tttcagtggg aagccgaggc ctggcgattg 3000tatctcgtgc tttactatgt tgtctgcatc ggcctgttca tcttctgtct cgatggtggt 3060catgctgacg agccctcgcg ggaggcaagt ccagacctcg gcgcggcagg ggcggagctc 3120gaggacgaga gcgcgcaggc tggagctgtc cagggtcctg agacgctgcg gactcaggtt 3180agtaggcagt gtcaggagat taacttgcat gatcttttgg agggcgtgcg ggaggttcag 3240atagtacttg atctcaacgg gtccgttggt ggagatgtcg atggcttgca gggttccgtg 3300tcccttgggc gctaccaccg tgcccttgtt tttcattttg gacggcggtg gctctgttgc 3360ttcttgcatg tttagaagcg gtgtcgaggg cgcgcaccgg gcggcagggg cggctcggga 3420cccggcggca tggctggcag tggtacgtcg gcgccgcgcg cgggtaggtt ctggtactgc 3480gccctgagaa gactcgcatg cgcgacgacg cggcggttga catcctggat ctgacgcctc 3540tgggtgaaag ctaccggccc cgtgagcttg aacctgaaag agagttcaac agaatcaatc 3600tcggtatcgt tgacggcggc ttgcctaagg atttcttgca cgtcaccaga gttgtcctgg 3660taggcgatct ccgccatgaa ctgctcgatc tcttcctctt gaagatctcc gcggcccgct 3720ctctcgacgg tggccgcgag gtcgttggag atgcgcccaa tgagttgaga gaatgcattc 3780atgcccgcct cgttccagac gcggctgtag accacggccc ccacgggatc tctcgcgcgc 3840atgaccacct gggcgaggtt gagctccacg tggcgggtga agaccgcata gttgcatagg 3900cgctggaaaa ggtagttgag tgtggtggcg atgtgctcgg tgacgaagaa atacatgatc 3960catcgtctca gcggcatctc gctgacatcg cccagagctt ccaagcgctc catggcctcg 4020tagaagtcca cggcaaaatt aaaaaactgg gagtttcgcg cggacacggt caactcctct 4080tccagaagac ggataagttc ggcgatggtg gtgcgcacct cgcgctcgaa agcccctggg 4140atttcttcct caatctcttc ttcttccact aacatctctt cctcttcagg tggggctgca 4200ggaggagggg gaacgcggcg acgccggcgg cgcacgggca gacggtcgat gaatctttca 4260atgacctctc cgcggcggcg gcgcatggtt tcagtgacgg cgcggccgtt ctcgcgcggt 4320cgcagagtaa aaacaccgcc gcgcatctcc ttaaagtggt gactgggagg ttctccgttt 4380gggagggaga gggcgctgat tatacatttt attaattggc ccgtagggac tgcacgcaga 4440gatctgatcg tgtcaagatc cacgggatct gaaaaccttt cgacgaaagc gtctaaccag 4500tcacagtcac aaggtaggct gagtacggct tcttgtgggc gggggtggtt atgtgttcgg 4560tctgggtctt ctgtttcttc ttcatctcgg gaaggtgaga cgatgctgct ggtgatgaaa 4620ttaaagtagg cagttctaag acggcggatg gtggcgagga gcaccaggtc tttgggtccg 4680gcttgctgga tacgcaggcg attggccatt ccccaagcat tatcctgaca tctagcaaga 4740tctttgtagt agtcttgcat gagccgttct acgggcactt cttcctcacc cgttctgcca 4800tgcatacgtg tgagtccaaa tccgcgcatt ggttgtacca gtgccaagtc agctacgact 4860ctttcggcga ggatggcttg ctgtacttgg gtaagggtgg cttgaaagtc atcaaaatcc 4920acaaagcggt ggtaagctcc tgtattaatg gtgtaagcac agttggccat gactgaccag 4980ttaactgtct ggtgaccagg gcgcacgagc tcggtgtatt taaggcgcga ataggcgcgg 5040gtgtcaaaga tgtaatcgtt gcaggtgcgc accagatact ggtaccctat aagaaaatgc 5100ggcggtggtt ggcggtagag aggccatcgt tctgtagctg gagcgccagg ggcgaggtct 5160tccaacataa ggcggtgata gccgtagatg tacctggaca tccaggtgat tcctgcggcg 5220gtagtagaag cccgaggaaa ctcgcgtacg cggttccaaa tgttgcgtag cggcatgaag 5280tagttcat 528823981DNAArtificial SequenceE3 REGION FROM ENAD 23atgtctggtg acgcggctga gctatctcgg ctgcgacatc tagaccactg ccgccgcttt 60cgctgctttg cccgggaact cattgagttc atctacttcg aactccccaa ggatcaccct 120caaggtccgg cccacggagt gcggatttct atcgaaggca aaatagactc tcgcctgcaa 180cgaattttct cccagcggcc cgtgctgatc gagcgagacc agggaaacac cacggtttcc 240atctactgca tttgtaatca ccccggattg catgaaagcc tttgctgtct tatgtgtact 300gagtttaata aaaactgaat taagactctc ctacggactg ccgcttcttc aacccggatt 360ttacaaccag aagaacgaaa cttttcctgt cgtccaggac tctgttaact tcacctttcc 420tactcacaaa ctagaagctc aacgactaca ccgcttttcc agaagcattt tccctactaa 480tactactttc aaaaccggag gtgagctcca aggtcttcct acagaaaacc cttgggtgga 540agcgggcctt gtagtgctag gaattcttgc gggtgggctt gtgattattc tttgctacct 600atacacacct tgcttcactt tcttagtggt gttgtggtat tggtttaaaa aatggggccc 660atactagtct tgcttgtttt actttcgctt ttggaaccgg gttctgccaa ttacgatcca 720tgtctagact tcgacccaga aaactgcaca cttacttttg cacccgacac aagccgcatc 780tgtggagttc atcgcctctc ttacgaactt ggcccccaac gacaaaaatt tacctgcatg 840gtgggaatca accccatagt tatcacccag caaagtggag atactaaggg ttgcattcac 900tgctcctgcg attccatcga gtgcacctac accctgctga agaccctatg cggcctaaga 960gacctgctac caatgaatta a 98124201DNAArtificial SequenceA NON-CODING SEQUENCE SUITABLE FOR INCLUSION INTO BX 24aaaatgatta ataaaaaatc acttacttga aatcagcaat aaggtctctg ttgaaatttt 60ctcccagcag cacctcactt ccctcttccc aactctggta ttctaaaccc cgttcagcgg 120catactttct ccatacttta aaggggatgt caaattttag ctcctctcct gtacccacaa 180tcttcatgtc tttcttccca g 2012534DNAArtificial SequenceA NON-CODING SEQUENCE SUITABLE FOR INCLUSION INTO BY 25caaataaagt ttaacttgtt tatttgaaaa tcaa 34268PRTArtificial SequenceHinge linker sequences 26Asp Lys Thr His Thr Cys Ala Ala1 52711PRTArtificial SequenceHinge linker sequence 27Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala1 5 102818PRTArtificial SequenceHinge linker sequence 28Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Thr Cys Pro Pro Cys1 5 10 15Pro Ala2925PRTArtificial SequenceHinge linker sequence 29Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Thr Cys Pro Pro Cys1 5 10 15Pro Ala Thr Cys Pro Pro Cys Pro Ala 20 253030PRTArtificial SequenceHinge linker sequence 30Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Gly Lys Pro Thr Leu1 5 10 15Tyr Asn Ser Leu Val Met Ser Asp Thr Ala Gly Thr Cys Tyr 20 25 303131PRTArtificial SequenceHinge linker sequence 31Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Gly Lys Pro Thr His1 5 10 15Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr Cys Tyr 20 25 303215PRTArtificial SequenceHinge linker sequence 32Asp Lys Thr His Thr Cys Cys Val Glu Cys Pro Pro Cys Pro Ala1 5 10 153326PRTArtificial SequenceHinge linker sequence 33Asp Lys Thr His Thr Cys Pro Arg Cys Pro Glu Pro Lys Ser Cys Asp1 5 10 15Thr Pro Pro Pro Cys Pro Arg Cys Pro Ala 20 253411PRTArtificial SequenceHinge linker sequence 34Asp Lys Thr His Thr Cys Pro Ser Cys Pro Ala1 5 10357PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 35Ser Gly Gly Gly Gly Ser Glu1 5366PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 36Asp Lys Thr His Thr Ser1 5376PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 37Ser Gly Gly Gly Gly Ser1 53811PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 38Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 103916PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 39Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 10 154021PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 40Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 10 15Gly Gly Gly Gly Ser 204126PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 41Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 10 15Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 254211PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 42Ala Ala Ala Gly Ser Gly Gly Ala Ser Ala Ser1 5 104316PRTArtificial SequenceFLEXIBLE LINKER SEQUENCEmisc_feature(7)..(7)Xaa can be any naturally occurring amino acid 43Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Gly Ala Ser Ala Ser1 5 10 154421PRTArtificial SequenceFLEXIBLE LINKER SEQUENCEmisc_feature(7)..(7)Xaa can be any naturally occurring amino acidmisc_feature(12)..(12)Xaa can be any naturally occurring amino acid 44Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser1 5 10 15Gly Ala Ser Ala Ser 204526PRTArtificial SequenceFLEXIBLE LINKER SEQUENCEmisc_feature(7)..(7)Xaa can be any naturally occurring amino acidmisc_feature(12)..(12)Xaa can be any naturally occurring amino acidmisc_feature(17)..(17)Xaa can be any naturally occurring amino acid 45Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser1 5 10 15Xaa Gly Gly Gly Ser Gly Ala Ser Ala Ser 20 254631PRTArtificial SequenceFLEXIBLE LINKER SEQUENCEmisc_feature(7)..(7)Xaa can be any naturally occurring amino acidmisc_feature(12)..(12)Xaa can be any naturally occurring amino acidmisc_feature(17)..(17)Xaa can be any naturally occurring amino acidmisc_feature(22)..(22)Xaa can be any naturally occurring amino acid 46Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser1 5 10 15Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser Gly Ala Ser Ala Ser 20 25 304713PRTArtificial SequenceFLEXIBLE LINKER SEQUENCEmisc_feature(7)..(7)Xaa can be any naturally occurring amino acid 47Ala Ala Ala Gly Ser Gly Xaa Ser Gly Ala Ser Ala Ser1 5 104828PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 48Pro Gly Gly Asn Arg Gly Thr Thr Thr Thr Arg Arg Pro Ala Thr Thr1 5 10 15Thr Gly Ser Ser Pro Gly Pro Thr Gln Ser His Tyr 20 254911PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 49Ala Thr Thr Thr Gly Ser Ser Pro Gly Pro Thr1 5 10506PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 50Ala Thr Thr Thr Gly Ser1 55121PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 51Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Ser Pro Pro Ser Lys Glu1 5 10 15Ser His Lys Ser Pro 205215PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 52Gly Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp1 5 10 155315PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 53Gly Gly Gly Gly Ile Ala Pro Ser Met Val Gly Gly Gly Gly Ser1 5 10 155415PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 54Gly Gly Gly Gly Lys Val Glu Gly Ala Gly Gly Gly Gly Gly Ser1 5 10 155515PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 55Gly Gly Gly Gly Ser Met Lys Ser His Asp Gly Gly Gly Gly Ser1 5 10 155615PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 56Gly Gly Gly Gly Asn Leu Ile Thr Ile Val Gly Gly Gly Gly Ser1

5 10 155715PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 57Gly Gly Gly Gly Val Val Pro Ser Leu Pro Gly Gly Gly Gly Ser1 5 10 155812PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 58Gly Gly Glu Lys Ser Ile Pro Gly Gly Gly Gly Ser1 5 105918PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 59Arg Pro Leu Ser Tyr Arg Pro Pro Phe Pro Phe Gly Phe Pro Ser Val1 5 10 15Arg Pro6018PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 60Tyr Pro Arg Ser Ile Tyr Ile Arg Arg Arg His Pro Ser Pro Ser Leu1 5 10 15Thr Thr6118PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 61Thr Pro Ser His Leu Ser His Ile Leu Pro Ser Phe Gly Leu Pro Thr1 5 10 15Phe Asn6218PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 62Arg Pro Val Ser Pro Phe Thr Phe Pro Arg Leu Ser Asn Ser Trp Leu1 5 10 15Pro Ala6318PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 63Ser Pro Ala Ala His Phe Pro Arg Ser Ile Pro Arg Pro Gly Pro Ile1 5 10 15Arg Thr6418PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 64Ala Pro Gly Pro Ser Ala Pro Ser His Arg Ser Leu Pro Ser Arg Ala1 5 10 15Phe Gly6518PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 65Pro Arg Asn Ser Ile His Phe Leu His Pro Leu Leu Val Ala Pro Leu1 5 10 15Gly Ala6618PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 66Met Pro Ser Leu Ser Gly Val Leu Gln Val Arg Tyr Leu Ser Pro Pro1 5 10 15Asp Leu6718PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 67Ser Pro Gln Tyr Pro Ser Pro Leu Thr Leu Thr Leu Pro Pro His Pro1 5 10 15Ser Leu6818PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 68Asn Pro Ser Leu Asn Pro Pro Ser Tyr Leu His Arg Ala Pro Ser Arg1 5 10 15Ile Ser6917PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 69Leu Pro Trp Arg Thr Ser Leu Leu Pro Ser Leu Pro Leu Arg Arg Arg1 5 10 15Pro7018PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 70Pro Pro Leu Phe Ala Lys Gly Pro Val Gly Leu Leu Ser Arg Ser Phe1 5 10 15Pro Pro7118PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 71Val Pro Pro Ala Pro Val Val Ser Leu Arg Ser Ala His Ala Arg Pro1 5 10 15Pro Tyr7217PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 72Leu Arg Pro Thr Pro Pro Arg Val Arg Ser Tyr Thr Cys Cys Pro Thr1 5 10 15Pro7318PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 73Pro Asn Val Ala His Val Leu Pro Leu Leu Thr Val Pro Trp Asp Asn1 5 10 15Leu Arg7418PRTArtificial SequenceFLEXIBLE LINKER SEQUENCE 74Cys Asn Pro Leu Leu Pro Leu Cys Ala Arg Ser Pro Ala Val Arg Thr1 5 10 15Phe Pro7511PRTArtificial SequenceRigid linker sequence 75Gly Ala Pro Ala Pro Ala Ala Pro Ala Pro Ala1 5 10764PRTArtificial SequenceRigid linker sequence 76Pro Pro Pro Pro17711PRTArtificial SequenceLINKER SEQUENCE 77Asp Leu Cys Leu Arg Asp Trp Gly Cys Leu Trp1 5 107811PRTArtificial SequenceLINKER SEQUENCE 78Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp1 5 107915PRTArtificial SequenceLINKER SEQUENCE 79Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Gly Asp1 5 10 158020PRTArtificial SequenceLINKER SEQUENCE 80Gln Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp1 5 10 15Glu Asp Asp Glu 208120PRTArtificial SequenceLINKER SEQUENCE 81Gln Gly Leu Ile Gly Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp1 5 10 15Gly Arg Ser Val 208221PRTArtificial SequenceLINKER SEQUENCE 82Gln Gly Leu Ile Gly Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp1 5 10 15Gly Arg Ser Val Lys 208315PRTArtificial SequenceLINKER SEQUENCE 83Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu Asp Asp1 5 10 158418PRTArtificial SequenceLINKER SEQUENCE 84Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu1 5 10 15Asp Asp8516PRTArtificial SequenceLINKER SEQUENCE 85Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu Asp Asp1 5 10 158615PRTArtificial SequenceLINKER SEQUENCE 86Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu Asp1 5 10 158718PRTArtificial SequenceLINKER SEQUENCE 87Arg Leu Met Glu Asp Ile Cys Leu Ala Arg Trp Gly Cys Leu Trp Glu1 5 10 15Asp Asp8820PRTArtificial SequenceLINKER SEQUENCE 88Glu Val Arg Ser Phe Cys Thr Arg Trp Pro Ala Glu Lys Ser Cys Lys1 5 10 15Pro Leu Arg Gly 208920PRTArtificial SequenceLINKER SEQUENCE 89Arg Ala Pro Glu Ser Phe Val Cys Tyr Trp Glu Thr Ile Cys Phe Glu1 5 10 15Arg Ser Glu Gln 209011PRTArtificial SequenceLINKER SEQUENCE 90Glu Met Cys Tyr Phe Pro Gly Ile Cys Trp Met1 5 109120PRTArtificial SequencePDGFR RECEPTOR A 91Ala Val Leu Val Leu Leu Val Ile Val Ile Ile Ser Leu Ile Val Leu1 5 10 15Val Val Ile Trp 209221PRTArtificial SequencePDGFR RECEPTOR B 92Val Val Ile Ser Ala Ile Leu Ala Leu Val Val Leu Thr Ile Ile Ser1 5 10 15Leu Ile Ile Leu Ile 209324PRTArtificial SequenceINSULIN-LIKE GROWTH FACTOR 1 93Ile Ile Ile Gly Pro Pro Leu Ile Phe Val Phe Leu Phe Ser Val Val1 5 10 15Ile Gly Ser Ile Tyr Leu Phe Leu 209428PRTArtificial SequenceIL6-R 94Ser Ser Ser Val Pro Leu Pro Thr Phe Leu Val Ala Gly Gly Ser Leu1 5 10 15Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile Val Leu 20 259527PRTArtificial SequenceCD28 95Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu1 5 10 15Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 20 259634522DNAArtificial SequenceNG-348 virus genome sequence comprising a transgene cassette that encoding a membrane-anchored chimeric form an anti-human CD3e scFv, and CD80 inserted in the region BY 96tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg

caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg

caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300ccttatcatc ctcatcatgc tttggcagaa gaagccacgt ggaagcggag ctactaactt 30360cagcctgctg aagcaggctg gagacgtgga ggagaaccct ggacctggcc acacacggag 30420gcagggaaca tcaccatcca agtgtccata cctcaatttc tttcagctct tggtgctggc 30480tggtctttct cacttctgtt caggtgttat ccacgtgacc aaggaagtga aagaagtggc 30540aacgctgtcc tgtggtcaca atgtttctgt tgaagagctg gcacaaactc gcatctactg 30600gcaaaaggag aagaaaatgg tgctgactat gatgtctggg gacatgaata tatggcccga 30660gtacaagaac cggaccatct ttgatatcac taataacctc tccattgtga tcctggctct 30720gcgcccatct gacgagggca catacgagtg tgttgttctg aagtatgaaa aagacgcttt 30780caagcgggaa cacctggctg aagtgacgtt atcagtcaaa gctgacttcc ctacacctag 30840tatatctgac tttgaaattc caacttctaa tattagaagg ataatttgct caacctctgg 30900aggttttcca gagcctcacc tctcctggtt ggaaaatgga gaagaattaa atgccatcaa 30960cacaacagtt tcccaagatc ctgaaactga gctctatgct gttagcagca aactggattt 31020caatatgaca accaaccaca gcttcatgtg tctcatcaag tatggacatt taagagtgaa 31080tcagaccttc aactggaata caaccaagca agagcatttt cctgataacc tgctcccatc 31140ctgggccatt accttaatct cagtaaatgg aatttttgtg atatgctgcc tgacctactg 31200ctttgcccca agatgcagag agagaaggag gaatgagaga ttgagaaggg aaagtgtacg 31260ccctgtataa gctagcttga ctgactgaga tacagcgtac cttcagctca cagacatgat 31320aagatacatt gatgagtttg gacaaaccac aactagaatg cagtgaaaaa aatgctttat 31380ttgtgaaatt tgtgatgcta ttgctttatt tgtaaccatt ataagctgca ataaacaagt 31440taacaacaac aattgcattc attttatgtt tcaggttcag ggggaggtgt gggaggtttt 31500ttaaagcaag taaaacctct acaaatgtgg tagtcgtcag ctatcctgca ggaacttgtt 31560tatttgaaaa tcaattcaca aaatccgagt agttattttg cctccccctt cccatttaac 31620agaatacacc aatctctccc cacgcacagc tttaaacatt tggataccat tagatataga 31680catggtttta gattccacat tccaaacagt ttcagagcga gccaatctgg ggtcagtgat 31740agataaaaat ccatcgggat agtcttttaa agcgctttca cagtccaact gctgcggatg 31800cgactccgga gtctggatca cggtcatctg gaagaagaac gatgggaatc ataatccgaa 31860aacggtatcg gacgattgtg tctcatcaaa cccacaagca gccgctgtct gcgtcgctcc 31920gtgcgactgc tgtttatggg atcagggtcc acagtgtcct gaagcatgat tttaatagcc 31980cttaacatca actttctggt gcgatgcgcg cagcaacgca ttctgatttc actcaaatct 32040ttgcagtagg tacaacacat tattacaata ttgtttaata aaccataatt aaaagcgctc 32100cagccaaaac tcatatctga tataatcgcc cctgcatgac catcatacca aagtttaata 32160taaattaaat gacgttccct caaaaacaca ctacccacat acatgatctc ttttggcatg 32220tgcatattaa caatctgtct gtaccatgga caacgttggt taatcatgca acccaatata 32280accttccgga accacactgc caacaccgct cccccagcca tgcattgaag tgaaccctgc 32340tgattacaat gacaatgaag aacccaattc tctcgaccgt gaatcacttg agaatgaaaa 32400atatctatag tggcacaaca tagacataaa tgcatgcatc ttctcataat ttttaactcc 32460tcaggattta gaaacatatc ccagggaata ggaagctctt gcagaacagt aaagctggca 32520gaacaaggaa gaccacgaac acaacttaca ctatgcatag tcatagtatc acaatctggc 32580aacagcgggt ggtcttcagt catagaagct cgggtttcat tttcctcaca acgtggtaac 32640tgggctctgg tgtaagggtg atgtctggcg catgatgtcg agcgtgcgcg caaccttgtc 32700ataatggagt tgcttcctga cattctcgta ttttgtatag caaaacgcgg ccctggcaga 32760acacactctt cttcgccttc tatcctgccg cttagcgtgt tccgtgtgat agttcaagta 32820caaccacact cttaagttgg tcaaaagaat gctggcttca gttgtaatca aaactccatc 32880gcatctaatc gttctgagga aatcatccaa gcaatgcaac tggattgtgt ttcaagcagg 32940agaggagagg gaagagacgg aagaaccatg ttaattttta ttccaaacga tctcgcagta 33000cttcaaattg tagatcgcgc agatggcatc tctcgccccc actgtgttgg tgaaaaagca 33060cagctagatc aaaagaaatg cgattttcaa ggtgctcaac ggtggcttcc agcaaagcct 33120ccacgcgcac atccaagaac aaaagaatac caaaagaagg agcattttct aactcctcaa 33180tcatcatatt acattcctgc accattccca gataattttc agctttccag ccttgaatta 33240ttcgtgtcag ttcttgtggt aaatccaatc cacacattac aaacaggtcc cggagggcgc 33300cctccaccac cattcttaaa cacaccctca taatgacaaa atatcttgct cctgtgtcac 33360ctgtagcgaa ttgagaatgg caacatcaat tgacatgccc ttggctctaa gttcttcttt 33420aagttctagt tgtaaaaact ctctcatatt atcaccaaac tgcttagcca gaagcccccc 33480gggaacaaga gcaggggacg ctacagtgca gtacaagcgc agacctcccc aattggctcc 33540agcaaaaaca agattggaat aagcatattg ggaaccgcca gtaatatcat cgaagttgct 33600ggaaatataa tcaggcagag tttcttgtaa aaattgaata aaagaaaaat ttgccaaaaa 33660aacattcaaa acctctggga tgcaaatgca ataggttacc gcgctgcgct ccaacattgt 33720tagttttgaa ttagtctgca aaaataaaaa aaaaaacaag cgtcatatca tagtagcctg 33780acgaacagat ggataaatca gtctttccat cacaagacaa gccacagggt ctccagctcg 33840accctcgtaa aacctgtcat catgattaaa caacagcacc gaaagttcct cgcggtgacc 33900agcatgaata attcttgatg aagcatacaa tccagacatg ttagcatcag ttaacgagaa 33960aaaacagcca acatagcctt tgggtataat tatgcttaat cgtaagtata gcaaagccac 34020ccctcgcgga tacaaagtaa aaggcacagg agaataaaaa atataattat ttctctgctg 34080ctgttcaggc aacgtcgccc ccggtccctc taaatacaca tacaaagcct catcagccat 34140ggcttaccag acaaagtaca gcgggcacac aaagcacaag ctctaaagtg actctccaac 34200ctctccacaa tatatatata cacaagccct aaactgacgt aatgggagta aagtgtaaaa 34260aatcccgcca aacccaacac acaccccgaa actgcgtcac cagggaaaag tacagtttca 34320cttccgcaat cccaacaggc gtaacttcct ctttctcacg gtacgtgata tcccactaac 34380ttgcaacgtc attttcccac ggtcgcaccg ccccttttag ccgttaaccc cacagccaat 34440caccacacga tccacacttt ttaaaatcac ctcatttaca tattggcacc attccatcta 34500taaggtatat tatatagata ga 3452297966DNAArtificial SequenceMEMBRANE TETHERED OKT3-SCFV NUCLEIC ACID SEQUENCE 97atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactcccag 60gtgcagctgc agcagtctgg ggctgaactg gcaagacctg gggcctcagt gaagatgtcc 120tgcaaggctt ctggctacac ctttactagg tacacgatgc actgggtaaa acagaggcct 180ggacagggtc tggaatggat tggatacatt aatcctagcc gtggttatac taattacaat 240cagaagttca aggacaaggc cacattgact acagacaaat cctccagcac agcctacatg 300caactgagca gcctgacatc tgaggactct gcagtctatt actgtgcaag atattatgat 360gatcattact gccttgacta ctggggccaa ggcaccactc tcacagtctc ctcaggtggc 420ggtggctcgg gcggtggtgg atctggtggc ggcggatctg atatcgtgct cactcagtct 480ccagcaatca tgtctgcatc tccaggggag aaggtcacca tgacctgcag tgccagctca 540agtgtaagtt acatgaactg gtaccagcag aagtcaggca cctcccccaa aagatggatt 600tatgacacat ccaaactggc ttctggagtc cctgctcact tcaggggcag tgggtctggg 660acctcttact ctctcacaat cagcggcatg gaggctgaag atgctgccac ttattactgc 720cagcagtgga gtagtaaccc attcacgttc ggctcgggga caaagttgga aataaaccgg 780ggatccgaac aaaaactcat ctcagaagag gatctgaatg ctgtgggcca ggacacgcag 840gaggtcatcg tggtgccaca ctccttgccc tttaaggtgg tggtgatctc agccatcctg 900gccctggtgg tgctcaccat catctccctt atcatcctca tcatgctttg gcagaagaag 960ccacgt 966982196DNAArtificial SequenceTransgene Cassette sequence - NG-348 98gcgatcgcca ggcccaccat gggatggagc tgtatcatcc tcttcttggt agcaacagct 60acaggtgtcc actcccaggt gcagctgcag cagtctgggg ctgaactggc aagacctggg 120gcctcagtga agatgtcctg caaggcttct ggctacacct ttactaggta cacgatgcac 180tgggtaaaac agaggcctgg acagggtctg gaatggattg gatacattaa tcctagccgt 240ggttatacta attacaatca gaagttcaag gacaaggcca cattgactac agacaaatcc 300tccagcacag cctacatgca actgagcagc ctgacatctg aggactctgc agtctattac 360tgtgcaagat attatgatga tcattactgc cttgactact ggggccaagg caccactctc 420acagtctcct caggtggcgg tggctcgggc ggtggtggat ctggtggcgg cggatctgat 480atcgtgctca ctcagtctcc agcaatcatg tctgcatctc caggggagaa ggtcaccatg 540acctgcagtg ccagctcaag tgtaagttac atgaactggt accagcagaa gtcaggcacc 600tcccccaaaa gatggattta tgacacatcc aaactggctt ctggagtccc tgctcacttc 660aggggcagtg ggtctgggac ctcttactct ctcacaatca gcggcatgga ggctgaagat 720gctgccactt attactgcca gcagtggagt agtaacccat tcacgttcgg ctcggggaca 780aagttggaaa taaaccgggg atccgaacaa aaactcatct cagaagagga tctgaatgct 840gtgggccagg acacgcagga ggtcatcgtg gtgccacact ccttgccctt taaggtggtg 900gtgatctcag ccatcctggc cctggtggtg ctcaccatca tctcccttat catcctcatc 960atgctttggc agaagaagcc acgtggaagc ggagctacta acttcagcct gctgaagcag 1020gctggagacg tggaggagaa ccctggacct ggccacacac ggaggcaggg aacatcacca 1080tccaagtgtc catacctcaa tttctttcag ctcttggtgc tggctggtct ttctcacttc 1140tgttcaggtg ttatccacgt gaccaaggaa gtgaaagaag tggcaacgct gtcctgtggt 1200cacaatgttt ctgttgaaga gctggcacaa actcgcatct actggcaaaa ggagaagaaa 1260atggtgctga ctatgatgtc tggggacatg aatatatggc ccgagtacaa gaaccggacc 1320atctttgata tcactaataa cctctccatt gtgatcctgg ctctgcgccc atctgacgag 1380ggcacatacg agtgtgttgt tctgaagtat gaaaaagacg ctttcaagcg ggaacacctg 1440gctgaagtga cgttatcagt caaagctgac ttccctacac ctagtatatc tgactttgaa 1500attccaactt ctaatattag aaggataatt tgctcaacct ctggaggttt tccagagcct 1560cacctctcct ggttggaaaa tggagaagaa ttaaatgcca tcaacacaac agtttcccaa 1620gatcctgaaa ctgagctcta tgctgttagc agcaaactgg atttcaatat gacaaccaac 1680cacagcttca tgtgtctcat caagtatgga catttaagag tgaatcagac cttcaactgg 1740aatacaacca agcaagagca ttttcctgat aacctgctcc catcctgggc cattacctta 1800atctcagtaa atggaatttt tgtgatatgc tgcctgacct actgctttgc cccaagatgc 1860agagagagaa ggaggaatga gagattgaga agggaaagtg tacgccctgt ataagctagc 1920ttgactgact gagatacagc gtaccttcag ctcacagaca tgataagata cattgatgag 1980tttggacaaa ccacaactag aatgcagtga aaaaaatgct ttatttgtga aatttgtgat 2040gctattgctt tatttgtaac cattataagc tgcaataaac aagttaacaa caacaattgc 2100attcatttta tgtttcaggt tcagggggag gtgtgggagg ttttttaaag caagtaaaac 2160ctctacaaat gtggtagtcg tcagctatcc tgcagg 219699333PRTArtificial SequenceMembrane anchored form of the anti-human CD3 single chain Fv with C-terminal V5 tag 99Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly1 5 10 15Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg 20 25 30Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn65 70 75 80Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser 85 90 95Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp 115 120 125Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 130 135 140Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser145 150 155 160Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys 165 170 175Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser 180 185 190Gly Thr Ser Pro Lys

Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser 195 200 205Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser 210 215 220Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys225 230 235 240Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu 245 250 255Glu Ile Asn Arg Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 260 265 270Asn Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser 275 280 285Leu Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val 290 295 300Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys305 310 315 320Pro Arg Gly Ser Ile Pro Asn Pro Leu Leu Gly Leu Asp 325 3301009PRTArtificial SequenceV5 tag (9 amino acid variant) 100Ile Pro Asn Pro Leu Leu Gly Leu Asp1 510134555DNAArtificial SequenceNG-348A virus genome sequence comprising a transgene cassette encoding a membrane-anchored chimeric form of the anti-human CD3e scFv with C-terminal V5 tag and CD80 inserted in the region BY 101tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag

tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta

ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300ccttatcatc ctcatcatgc tttggcagaa gaagccacgt ggttcaatcc ctaaccctct 30360cctcggtctc gatggaagcg gagctactaa cttcagcctg ctgaagcagg ctggagacgt 30420ggaggagaac cctggacctg gccacacacg gaggcaggga acatcaccat ccaagtgtcc 30480atacctcaat ttctttcagc tcttggtgct ggctggtctt tctcacttct gttcaggtgt 30540tatccacgtg accaaggaag tgaaagaagt ggcaacgctg tcctgtggtc acaatgtttc 30600tgttgaagag ctggcacaaa ctcgcatcta ctggcaaaag gagaagaaaa tggtgctgac 30660tatgatgtct ggggacatga atatatggcc cgagtacaag aaccggacca tctttgatat 30720cactaataac ctctccattg tgatcctggc tctgcgccca tctgacgagg gcacatacga 30780gtgtgttgtt ctgaagtatg aaaaagacgc tttcaagcgg gaacacctgg ctgaagtgac 30840gttatcagtc aaagctgact tccctacacc tagtatatct gactttgaaa ttccaacttc 30900taatattaga aggataattt gctcaacctc tggaggtttt ccagagcctc acctctcctg 30960gttggaaaat ggagaagaat taaatgccat caacacaaca gtttcccaag atcctgaaac 31020tgagctctat gctgttagca gcaaactgga tttcaatatg acaaccaacc acagcttcat 31080gtgtctcatc aagtatggac atttaagagt gaatcagacc ttcaactgga atacaaccaa 31140gcaagagcat tttcctgata acctgctccc atcctgggcc attaccttaa tctcagtaaa 31200tggaattttt gtgatatgct gcctgaccta ctgctttgcc ccaagatgca gagagagaag 31260gaggaatgag agattgagaa gggaaagtgt acgccctgta taagctagct tgactgactg 31320agatacagcg taccttcagc tcacagacat gataagatac attgatgagt ttggacaaac 31380cacaactaga atgcagtgaa aaaaatgctt tatttgtgaa atttgtgatg ctattgcttt 31440atttgtaacc attataagct gcaataaaca agttaacaac aacaattgca ttcattttat 31500gtttcaggtt cagggggagg tgtgggaggt tttttaaagc aagtaaaacc tctacaaatg 31560tggtagtcgt cagctatcct gcaggaactt gtttatttga aaatcaattc acaaaatccg 31620agtagttatt ttgcctcccc cttcccattt aacagaatac accaatctct ccccacgcac 31680agctttaaac atttggatac cattagatat agacatggtt ttagattcca cattccaaac 31740agtttcagag cgagccaatc tggggtcagt gatagataaa aatccatcgg gatagtcttt 31800taaagcgctt tcacagtcca actgctgcgg atgcgactcc ggagtctgga tcacggtcat 31860ctggaagaag aacgatggga atcataatcc gaaaacggta tcggacgatt gtgtctcatc 31920aaacccacaa gcagccgctg tctgcgtcgc tccgtgcgac tgctgtttat gggatcaggg 31980tccacagtgt cctgaagcat gattttaata gcccttaaca tcaactttct ggtgcgatgc 32040gcgcagcaac gcattctgat ttcactcaaa tctttgcagt aggtacaaca cattattaca 32100atattgttta ataaaccata attaaaagcg ctccagccaa aactcatatc tgatataatc 32160gcccctgcat gaccatcata ccaaagttta atataaatta aatgacgttc cctcaaaaac 32220acactaccca catacatgat ctcttttggc atgtgcatat taacaatctg tctgtaccat 32280ggacaacgtt ggttaatcat gcaacccaat ataaccttcc ggaaccacac tgccaacacc 32340gctcccccag ccatgcattg aagtgaaccc tgctgattac aatgacaatg aagaacccaa 32400ttctctcgac cgtgaatcac ttgagaatga aaaatatcta tagtggcaca acatagacat 32460aaatgcatgc atcttctcat aatttttaac tcctcaggat ttagaaacat atcccaggga 32520ataggaagct cttgcagaac agtaaagctg gcagaacaag gaagaccacg aacacaactt 32580acactatgca tagtcatagt atcacaatct ggcaacagcg ggtggtcttc agtcatagaa 32640gctcgggttt cattttcctc acaacgtggt aactgggctc tggtgtaagg gtgatgtctg 32700gcgcatgatg tcgagcgtgc gcgcaacctt gtcataatgg agttgcttcc tgacattctc 32760gtattttgta tagcaaaacg cggccctggc agaacacact cttcttcgcc ttctatcctg 32820ccgcttagcg tgttccgtgt gatagttcaa gtacaaccac actcttaagt tggtcaaaag 32880aatgctggct tcagttgtaa tcaaaactcc atcgcatcta atcgttctga ggaaatcatc 32940caagcaatgc aactggattg tgtttcaagc aggagaggag agggaagaga cggaagaacc 33000atgttaattt ttattccaaa cgatctcgca gtacttcaaa ttgtagatcg cgcagatggc 33060atctctcgcc cccactgtgt tggtgaaaaa gcacagctag atcaaaagaa atgcgatttt 33120caaggtgctc aacggtggct tccagcaaag cctccacgcg cacatccaag aacaaaagaa 33180taccaaaaga aggagcattt tctaactcct caatcatcat attacattcc tgcaccattc 33240ccagataatt ttcagctttc cagccttgaa ttattcgtgt cagttcttgt ggtaaatcca 33300atccacacat tacaaacagg tcccggaggg cgccctccac caccattctt aaacacaccc 33360tcataatgac aaaatatctt gctcctgtgt cacctgtagc gaattgagaa tggcaacatc 33420aattgacatg cccttggctc taagttcttc tttaagttct agttgtaaaa actctctcat 33480attatcacca aactgcttag ccagaagccc cccgggaaca agagcagggg acgctacagt 33540gcagtacaag cgcagacctc cccaattggc tccagcaaaa acaagattgg aataagcata 33600ttgggaaccg ccagtaatat catcgaagtt gctggaaata taatcaggca gagtttcttg 33660taaaaattga ataaaagaaa aatttgccaa aaaaacattc aaaacctctg ggatgcaaat 33720gcaataggtt accgcgctgc gctccaacat tgttagtttt gaattagtct gcaaaaataa 33780aaaaaaaaac aagcgtcata tcatagtagc ctgacgaaca gatggataaa tcagtctttc 33840catcacaaga caagccacag ggtctccagc tcgaccctcg taaaacctgt catcatgatt 33900aaacaacagc accgaaagtt cctcgcggtg accagcatga ataattcttg atgaagcata 33960caatccagac atgttagcat cagttaacga gaaaaaacag ccaacatagc ctttgggtat 34020aattatgctt aatcgtaagt atagcaaagc cacccctcgc ggatacaaag taaaaggcac 34080aggagaataa aaaatataat tatttctctg ctgctgttca ggcaacgtcg cccccggtcc 34140ctctaaatac acatacaaag cctcatcagc catggcttac cagacaaagt acagcgggca 34200cacaaagcac aagctctaaa gtgactctcc aacctctcca caatatatat atacacaagc 34260cctaaactga cgtaatggga gtaaagtgta aaaaatcccg ccaaacccaa cacacacccc 34320gaaactgcgt caccagggaa aagtacagtt tcacttccgc aatcccaaca ggcgtaactt 34380cctctttctc acggtacgtg atatcccact aacttgcaac gtcattttcc cacggtcgca 34440ccgccccttt tagccgttaa ccccacagcc aatcaccaca cgatccacac tttttaaaat 34500cacctcattt acatattggc accattccat ctataaggta tattatatag ataga 3455510233595DNAArtificial SequenceNG-420 virus genome sequence comprising a transgene cassette encoding a membrane-anchored chimeric form of the anti-human CD3e scFv inserted in the region BY 102tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa

cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc

ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300ccttatcatc ctcatcatgc tttggcagaa gaagccacgt taagctagct tgactgactg 30360agatacagcg taccttcagc tcacagacat gataagatac attgatgagt ttggacaaac 30420cacaactaga atgcagtgaa aaaaatgctt tatttgtgaa atttgtgatg ctattgcttt 30480atttgtaacc attataagct gcaataaaca agttaacaac aacaattgca ttcattttat 30540gtttcaggtt cagggggagg tgtgggaggt tttttaaagc aagtaaaacc tctacaaatg 30600tggtagtcgt cagctatcct gcaggaactt gtttatttga aaatcaattc acaaaatccg 30660agtagttatt ttgcctcccc cttcccattt aacagaatac accaatctct ccccacgcac 30720agctttaaac atttggatac cattagatat agacatggtt ttagattcca cattccaaac 30780agtttcagag cgagccaatc tggggtcagt gatagataaa aatccatcgg gatagtcttt 30840taaagcgctt tcacagtcca actgctgcgg atgcgactcc ggagtctgga tcacggtcat 30900ctggaagaag aacgatggga atcataatcc gaaaacggta tcggacgatt gtgtctcatc 30960aaacccacaa gcagccgctg tctgcgtcgc tccgtgcgac tgctgtttat gggatcaggg 31020tccacagtgt cctgaagcat gattttaata gcccttaaca tcaactttct ggtgcgatgc 31080gcgcagcaac gcattctgat ttcactcaaa tctttgcagt aggtacaaca cattattaca 31140atattgttta ataaaccata attaaaagcg ctccagccaa aactcatatc tgatataatc 31200gcccctgcat gaccatcata ccaaagttta atataaatta aatgacgttc cctcaaaaac 31260acactaccca catacatgat ctcttttggc atgtgcatat taacaatctg tctgtaccat 31320ggacaacgtt ggttaatcat gcaacccaat ataaccttcc ggaaccacac tgccaacacc 31380gctcccccag ccatgcattg aagtgaaccc tgctgattac aatgacaatg aagaacccaa 31440ttctctcgac cgtgaatcac ttgagaatga aaaatatcta tagtggcaca acatagacat 31500aaatgcatgc atcttctcat aatttttaac tcctcaggat ttagaaacat atcccaggga 31560ataggaagct cttgcagaac agtaaagctg gcagaacaag gaagaccacg aacacaactt 31620acactatgca tagtcatagt atcacaatct ggcaacagcg ggtggtcttc agtcatagaa 31680gctcgggttt cattttcctc acaacgtggt aactgggctc tggtgtaagg gtgatgtctg 31740gcgcatgatg tcgagcgtgc gcgcaacctt gtcataatgg agttgcttcc tgacattctc 31800gtattttgta tagcaaaacg cggccctggc agaacacact cttcttcgcc ttctatcctg 31860ccgcttagcg tgttccgtgt gatagttcaa gtacaaccac actcttaagt tggtcaaaag 31920aatgctggct tcagttgtaa tcaaaactcc atcgcatcta atcgttctga ggaaatcatc 31980caagcaatgc aactggattg tgtttcaagc aggagaggag agggaagaga cggaagaacc 32040atgttaattt ttattccaaa cgatctcgca gtacttcaaa ttgtagatcg cgcagatggc 32100atctctcgcc cccactgtgt tggtgaaaaa gcacagctag atcaaaagaa atgcgatttt 32160caaggtgctc aacggtggct tccagcaaag cctccacgcg cacatccaag aacaaaagaa 32220taccaaaaga aggagcattt tctaactcct caatcatcat attacattcc tgcaccattc 32280ccagataatt ttcagctttc cagccttgaa ttattcgtgt cagttcttgt ggtaaatcca 32340atccacacat tacaaacagg tcccggaggg cgccctccac caccattctt aaacacaccc 32400tcataatgac aaaatatctt gctcctgtgt cacctgtagc gaattgagaa tggcaacatc 32460aattgacatg cccttggctc taagttcttc tttaagttct agttgtaaaa actctctcat 32520attatcacca aactgcttag ccagaagccc cccgggaaca agagcagggg acgctacagt 32580gcagtacaag cgcagacctc cccaattggc tccagcaaaa acaagattgg aataagcata 32640ttgggaaccg ccagtaatat catcgaagtt gctggaaata taatcaggca gagtttcttg 32700taaaaattga ataaaagaaa aatttgccaa aaaaacattc aaaacctctg ggatgcaaat 32760gcaataggtt accgcgctgc gctccaacat tgttagtttt gaattagtct gcaaaaataa 32820aaaaaaaaac aagcgtcata tcatagtagc ctgacgaaca gatggataaa tcagtctttc 32880catcacaaga caagccacag ggtctccagc tcgaccctcg taaaacctgt catcatgatt 32940aaacaacagc accgaaagtt cctcgcggtg accagcatga ataattcttg atgaagcata 33000caatccagac atgttagcat cagttaacga gaaaaaacag ccaacatagc ctttgggtat 33060aattatgctt aatcgtaagt atagcaaagc cacccctcgc ggatacaaag taaaaggcac 33120aggagaataa aaaatataat tatttctctg ctgctgttca ggcaacgtcg cccccggtcc 33180ctctaaatac acatacaaag cctcatcagc catggcttac cagacaaagt acagcgggca 33240cacaaagcac aagctctaaa gtgactctcc aacctctcca caatatatat atacacaagc 33300cctaaactga cgtaatggga gtaaagtgta aaaaatcccg ccaaacccaa cacacacccc 33360gaaactgcgt caccagggaa aagtacagtt tcacttccgc aatcccaaca ggcgtaactt 33420cctctttctc acggtacgtg atatcccact aacttgcaac gtcattttcc cacggtcgca 33480ccgccccttt tagccgttaa ccccacagcc aatcaccaca cgatccacac tttttaaaat 33540cacctcattt acatattggc accattccat ctataaggta tattatatag ataga 3359510333628DNAArtificial SequenceNG-420 virus genome sequence comprising a transgene cassette encoding a membrane-anchored chimeric form of the anti-human CD3e scFv with a C-terminal V5 tag inserted in the region BY 103tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc

ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt

gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300ccttatcatc ctcatcatgc tttggcagaa gaagccacgt ggttcaatcc ctaaccctct 30360cctcggtctc gattaagcta gcttgactga ctgagataca gcgtaccttc agctcacaga 30420catgataaga tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg 30480ctttatttgt gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa 30540acaagttaac aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga 30600ggttttttaa agcaagtaaa acctctacaa atgtggtagt cgtcagctat cctgcaggaa 30660cttgtttatt tgaaaatcaa ttcacaaaat ccgagtagtt attttgcctc ccccttccca 30720tttaacagaa tacaccaatc tctccccacg cacagcttta aacatttgga taccattaga 30780tatagacatg gttttagatt ccacattcca aacagtttca gagcgagcca atctggggtc 30840agtgatagat aaaaatccat cgggatagtc ttttaaagcg ctttcacagt ccaactgctg 30900cggatgcgac tccggagtct ggatcacggt catctggaag aagaacgatg ggaatcataa 30960tccgaaaacg gtatcggacg attgtgtctc atcaaaccca caagcagccg ctgtctgcgt 31020cgctccgtgc gactgctgtt tatgggatca gggtccacag tgtcctgaag catgatttta 31080atagccctta acatcaactt tctggtgcga tgcgcgcagc aacgcattct gatttcactc 31140aaatctttgc agtaggtaca acacattatt acaatattgt ttaataaacc ataattaaaa 31200gcgctccagc caaaactcat atctgatata atcgcccctg catgaccatc ataccaaagt 31260ttaatataaa ttaaatgacg ttccctcaaa aacacactac ccacatacat gatctctttt 31320ggcatgtgca tattaacaat ctgtctgtac catggacaac gttggttaat catgcaaccc 31380aatataacct tccggaacca cactgccaac accgctcccc cagccatgca ttgaagtgaa 31440ccctgctgat tacaatgaca atgaagaacc caattctctc gaccgtgaat cacttgagaa 31500tgaaaaatat ctatagtggc acaacataga cataaatgca tgcatcttct cataattttt 31560aactcctcag gatttagaaa catatcccag ggaataggaa gctcttgcag aacagtaaag 31620ctggcagaac aaggaagacc acgaacacaa cttacactat gcatagtcat agtatcacaa 31680tctggcaaca gcgggtggtc ttcagtcata gaagctcggg tttcattttc ctcacaacgt 31740ggtaactggg ctctggtgta agggtgatgt ctggcgcatg atgtcgagcg tgcgcgcaac 31800cttgtcataa tggagttgct tcctgacatt ctcgtatttt gtatagcaaa acgcggccct 31860ggcagaacac actcttcttc gccttctatc ctgccgctta gcgtgttccg tgtgatagtt 31920caagtacaac cacactctta agttggtcaa aagaatgctg gcttcagttg taatcaaaac 31980tccatcgcat ctaatcgttc tgaggaaatc atccaagcaa tgcaactgga ttgtgtttca 32040agcaggagag gagagggaag agacggaaga accatgttaa tttttattcc aaacgatctc 32100gcagtacttc aaattgtaga tcgcgcagat ggcatctctc gcccccactg tgttggtgaa 32160aaagcacagc tagatcaaaa gaaatgcgat tttcaaggtg ctcaacggtg gcttccagca 32220aagcctccac gcgcacatcc aagaacaaaa gaataccaaa agaaggagca ttttctaact 32280cctcaatcat catattacat tcctgcacca ttcccagata attttcagct ttccagcctt 32340gaattattcg tgtcagttct tgtggtaaat ccaatccaca cattacaaac aggtcccgga 32400gggcgccctc caccaccatt cttaaacaca ccctcataat gacaaaatat cttgctcctg 32460tgtcacctgt agcgaattga gaatggcaac atcaattgac atgcccttgg ctctaagttc 32520ttctttaagt tctagttgta aaaactctct catattatca ccaaactgct tagccagaag 32580ccccccggga acaagagcag gggacgctac agtgcagtac aagcgcagac ctccccaatt 32640ggctccagca aaaacaagat tggaataagc atattgggaa ccgccagtaa tatcatcgaa 32700gttgctggaa atataatcag gcagagtttc ttgtaaaaat tgaataaaag aaaaatttgc 32760caaaaaaaca ttcaaaacct ctgggatgca aatgcaatag gttaccgcgc tgcgctccaa 32820cattgttagt tttgaattag tctgcaaaaa taaaaaaaaa aacaagcgtc atatcatagt 32880agcctgacga acagatggat aaatcagtct ttccatcaca agacaagcca cagggtctcc 32940agctcgaccc tcgtaaaacc tgtcatcatg attaaacaac agcaccgaaa gttcctcgcg 33000gtgaccagca tgaataattc ttgatgaagc atacaatcca gacatgttag catcagttaa 33060cgagaaaaaa cagccaacat agcctttggg tataattatg cttaatcgta agtatagcaa 33120agccacccct cgcggataca aagtaaaagg cacaggagaa taaaaaatat aattatttct 33180ctgctgctgt tcaggcaacg tcgcccccgg tccctctaaa tacacataca aagcctcatc 33240agccatggct taccagacaa agtacagcgg gcacacaaag cacaagctct aaagtgactc 33300tccaacctct ccacaatata tatatacaca agccctaaac tgacgtaatg ggagtaaagt 33360gtaaaaaatc ccgccaaacc caacacacac cccgaaactg cgtcaccagg gaaaagtaca 33420gtttcacttc cgcaatccca acaggcgtaa cttcctcttt ctcacggtac gtgatatccc 33480actaacttgc aacgtcattt tcccacggtc gcaccgcccc ttttagccgt taaccccaca 33540gccaatcacc acacgatcca cactttttaa aatcacctca tttacatatt ggcaccattc 33600catctataag gtatattata tagataga 3362810415PRTArtificial SequenceLinker 104Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 10 1510513RNAArtificial SequenceSequence comprising a start codon 105gccgccrcca ugg 1310610PRTArtificial Sequencec-myc tag 106Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu1 5 1010713PRTArtificial Sequencec-myc tag with amino acid spacer at the N and C-terminal 107Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn1 5 1010862PRTArtificial Sequencespacer - c-myc tag -spacer PDGF TM domain 108Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Ala Val Gly1 5 10 15Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser Leu Pro Phe Lys 20 25 30Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val Leu Thr Ile Ile 35 40 45Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys Pro Arg 50 55 6010932345DNAArtificial SequenceFully synthetic EnAd genome with incorporated cloning site for transgene cassette insertion as in plasmid pEnAd2.4 109tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960aaaggagcag tccatgcaga

ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11100gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020ggaagaaatg ctgcaggtta

tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18120acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24240tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25140atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340ctgacaaata aagtttgcga tcgctaccct gcaggaactt gtttatttga aaatcaattc 29400acaaaatccg agtagttatt ttgcctcccc cttcccattt aacagaatac accaatctct 29460ccccacgcac agctttaaac atttggatac cattagatat agacatggtt ttagattcca 29520cattccaaac agtttcagag cgagccaatc tggggtcagt gatagataaa aatccatcgg 29580gatagtcttt taaagcgctt tcacagtcca actgctgcgg atgcgactcc ggagtctgga 29640tcacggtcat ctggaagaag aacgatggga atcataatcc gaaaacggta tcggacgatt 29700gtgtctcatc aaacccacaa gcagccgctg tctgcgtcgc tccgtgcgac tgctgtttat 29760gggatcaggg tccacagtgt cctgaagcat gattttaata gcccttaaca tcaactttct 29820ggtgcgatgc gcgcagcaac gcattctgat ttcactcaaa tctttgcagt aggtacaaca 29880cattattaca atattgttta ataaaccata attaaaagcg ctccagccaa aactcatatc 29940tgatataatc gcccctgcat gaccatcata ccaaagttta atataaatta aatgacgttc 30000cctcaaaaac acactaccca catacatgat ctcttttggc atgtgcatat taacaatctg 30060tctgtaccat ggacaacgtt ggttaatcat gcaacccaat ataaccttcc ggaaccacac 30120tgccaacacc gctcccccag ccatgcattg aagtgaaccc tgctgattac aatgacaatg 30180aagaacccaa ttctctcgac cgtgaatcac ttgagaatga aaaatatcta tagtggcaca 30240acatagacat aaatgcatgc atcttctcat aatttttaac tcctcaggat ttagaaacat 30300atcccaggga ataggaagct cttgcagaac agtaaagctg gcagaacaag gaagaccacg 30360aacacaactt acactatgca tagtcatagt atcacaatct ggcaacagcg ggtggtcttc 30420agtcatagaa gctcgggttt cattttcctc acaacgtggt aactgggctc tggtgtaagg 30480gtgatgtctg gcgcatgatg tcgagcgtgc gcgcaacctt gtcataatgg agttgcttcc 30540tgacattctc gtattttgta tagcaaaacg cggccctggc agaacacact cttcttcgcc 30600ttctatcctg ccgcttagcg tgttccgtgt gatagttcaa gtacaaccac actcttaagt 30660tggtcaaaag aatgctggct tcagttgtaa tcaaaactcc atcgcatcta atcgttctga 30720ggaaatcatc caagcaatgc aactggattg tgtttcaagc aggagaggag agggaagaga 30780cggaagaacc atgttaattt ttattccaaa cgatctcgca gtacttcaaa ttgtagatcg 30840cgcagatggc atctctcgcc cccactgtgt tggtgaaaaa gcacagctag atcaaaagaa 30900atgcgatttt caaggtgctc aacggtggct tccagcaaag cctccacgcg cacatccaag 30960aacaaaagaa taccaaaaga aggagcattt tctaactcct caatcatcat attacattcc 31020tgcaccattc ccagataatt ttcagctttc cagccttgaa ttattcgtgt cagttcttgt 31080ggtaaatcca atccacacat

tacaaacagg tcccggaggg cgccctccac caccattctt 31140aaacacaccc tcataatgac aaaatatctt gctcctgtgt cacctgtagc gaattgagaa 31200tggcaacatc aattgacatg cccttggctc taagttcttc tttaagttct agttgtaaaa 31260actctctcat attatcacca aactgcttag ccagaagccc cccgggaaca agagcagggg 31320acgctacagt gcagtacaag cgcagacctc cccaattggc tccagcaaaa acaagattgg 31380aataagcata ttgggaaccg ccagtaatat catcgaagtt gctggaaata taatcaggca 31440gagtttcttg taaaaattga ataaaagaaa aatttgccaa aaaaacattc aaaacctctg 31500ggatgcaaat gcaataggtt accgcgctgc gctccaacat tgttagtttt gaattagtct 31560gcaaaaataa aaaaaaaaac aagcgtcata tcatagtagc ctgacgaaca gatggataaa 31620tcagtctttc catcacaaga caagccacag ggtctccagc tcgaccctcg taaaacctgt 31680catcatgatt aaacaacagc accgaaagtt cctcgcggtg accagcatga ataattcttg 31740atgaagcata caatccagac atgttagcat cagttaacga gaaaaaacag ccaacatagc 31800ctttgggtat aattatgctt aatcgtaagt atagcaaagc cacccctcgc ggatacaaag 31860taaaaggcac aggagaataa aaaatataat tatttctctg ctgctgttca ggcaacgtcg 31920cccccggtcc ctctaaatac acatacaaag cctcatcagc catggcttac cagacaaagt 31980acagcgggca cacaaagcac aagctctaaa gtgactctcc aacctctcca caatatatat 32040atacacaagc cctaaactga cgtaatggga gtaaagtgta aaaaatcccg ccaaacccaa 32100cacacacccc gaaactgcgt caccagggaa aagtacagtt tcacttccgc aatcccaaca 32160ggcgtaactt cctctttctc acggtacgtg atatcccact aacttgcaac gtcattttcc 32220cacggtcgca ccgccccttt tagccgttaa ccccacagcc aatcaccaca cgatccacac 32280tttttaaaat cacctcattt acatattggc accattccat ctataaggta tattatatag 32340ataga 32345

Claims

1.-23. (canceled)

24. A replication competent oncolytic group B adenovirus with selectivity for cancer cells, wherein the virus has a formula (I): 5'ITR-B.sub.1-B.sub.A-B.sub.2-B.sub.X-B.sub.B-B.sub.Y-B.sub.3-3'ITR (I) wherein: B.sub.1 comprises: E1A, E1B or E1A-E1B; B.sub.A is E2B-L1-L2-L3-E2A-L4; B.sub.2 is absent or comprises E3 or a transgene under an endogenous or exogenous promoter; B.sub.X is absent or a DNA sequence comprising: a restriction site, one or more transgenes or both; B.sub.B comprises L5; B.sub.Y comprises: a transgene encoding a B7 protein selected from B7-1 or an active fragment thereof, B7-2 or an active fragment thereof, or combinations thereof; and a second transgene; B.sub.3 is absent or comprises E4; wherein said transgenes in B.sub.Y are located between the stop codon-polyA recognition site of the adenovirus L5 gene and the stop codon-polyA recognition site of the adenovirus E4 gene, wherein said transgenes are under the control of the endogenous major late promoter.

25. A replication competent oncolytic virus according to claim 24, wherein B.sub.Y further comprises a third transgene.

26. A replication competent oncolytic virus according to claim 24, wherein the virus is a chimeric virus.

27. A replication competent oncolytic virus according to claim 26, wherein the virus backbone is enadenotucirev.

28. A replication competent oncolytic virus according to claim 24, wherein the B7-1 protein or active fragment thereof, B7-2 protein or active fragment, or combinations thereof, comprises a transmembrane sequence selected from the group comprising a transmembrane domain from a PDGF receptor, or a GPI anchor suitable for anchoring the protein or fragment in a cell membrane.

29. A replication competent oncolytic virus according to claim 24, wherein the second transgene encodes a polypeptide independently selected from the group comprising a cytokine, a chemokine, an antagonistic antibody molecule or fragment thereof, and an agonistic antibody molecule or fragment thereof.

30. A replication competent oncolytic virus according to claim 25, wherein the third transgene is independently selected from the group comprising a cytokine, a chemokine, an antagonistic antibody molecule or fragment thereof, and an agonistic antibody molecule or fragment thereof.

31. A replication competent oncolytic virus according to claim 24, wherein the second transgene encodes a cytokine independently selected from the group comprising IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15, and IL-12.

32. A replication competent oncolytic virus according to claim 25, wherein the third transgene encodes a cytokine independently selected from the group comprising IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15, and IL-12.

33. A replication competent oncolytic virus according to claim 24, wherein the second transgene encodes a chemokine selected from the group comprising MIP-1 alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21.

34. A replication competent oncolytic virus according to claim 25, wherein the third transgene encodes a chemokine selected from the group comprising MIP-1 alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21.

35. A replication competent oncolytic virus according to claim 34, wherein the second and third transgene encode Mip1.alpha. and IFN.alpha. respectively.

36. A replication competent oncolytic virus according to claim 35, wherein the B7 protein is B7-1 or an active fragment thereof.

37. A pharmaceutical composition comprising a replication competent oncolytic adenovirus according to claim 24, and a diluent or carrier.

38. A method of treating a patient comprising administering a therapeutically effective amount of a replication competent adenovirus according to claim 24.

39. A method of treating a patient comprising administering a therapeutically effective amount of a composition according to claim 37.

40. A method of treating a patient according claim 38, wherein the patient is a cancer patient.

41. A method of treating a patient according to claim 39, wherein the patient is a cancer patient.