MITIGATING TISSUE DAMAGE AND FIBROSIS VIA LATENT TRANSFORMING GROWTH FACTOR BETA BINDING PROTEIN (LTBP4)

Abstract

The disclosure relates to compositions and methods of mitigating tissue damage and fibrosis in a patient by modulating latent transforming growth factor beta binding protein (LTBP4)-induced proteolysis of a TGF.beta. superfamily protein.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a Continuation of U.S. application Ser. No. 16/392,108, filed Apr. 23, 2019, which is a Continuation of U.S. application Ser. No. 16/122,333, filed Sep. 5, 2018, which is a Continuation of U.S. application Ser. No. 15/857,122, filed Dec. 28, 2017, which is a Continuation of U.S. application Ser. No. 13/957,100, filed Aug. 1, 2013, which claims the priority benefit under 35 U.S.C. .sctn. 119(e) of Provisional U.S. Patent Application No. 61/678,564, filed Aug. 1, 2012, the disclosure of which is incorporated herein by reference in its entirety.

FIELD

[0003] The disclosure relates to compositions and methods of mitigating tissue damage and fibrosis in a patient via latent transforming growth factor beta binding protein (LTBP4).

SEQUENCE LISTING

[0004] This application contains, as a separate part of the disclosure, a Sequence Listing in computer-readable form (filename: 46577E_SeqListing.txt; created: Dec. 16, 2019; 220,992 bytes--ASCII text file) which is incorporated by reference in its entirety.

BACKGROUND

[0005] The transforming growth factor (TGF) beta superfamily proteins are key regulators of fibrosis in all parenchymal organs [Kisseleva et al., Proc Am Thorac Soc. 5: 338-42 (2008)]. Duchenne Muscular Dystrophy (DMD) is characterized by progressive fibrosis that is accompanied by increased TGF.beta. signaling [Bernasconi et al., J Clin Invest. 96: 1137-44 (1995); Chen et al., Neurology 65: 826-34 (2005)]. In DMD, fibrosis not only contributes directly to muscle dysfunction but also inhibits regeneration. DMD is characterized by muscle membrane fragility that leads to progressive myofiber loss. With disease progression, DMD muscle is replaced by fibrosis. Although muscle is highly regenerative, regeneration in DMD is not sufficient to offset degeneration leading to muscle weakness. Glucocorticoid steroids are used to slow progression in DMD, but use of steroids is complicated by side effects including osteoporosis and weight gain (Bushby et al., 2010). Experimental therapies for DMD include approaches to increase dystrophin expression, modulate the inflammatory response, promote muscle growth and reduce fibrosis [Bushby et al., Lancet 374: 1849-56 (2009)].

[0006] In recent years, biological compounds such as antibodies have shown efficacy for treating chronic diseases. For example, antibodies directed against TNF.alpha. (infliximab) or anti-TNF receptor (etanercept) are now in wide use for rheumatoid arthritis and other related disorders. While initially developed for its anti-cancer activity, the anti-VEGF antibody is now used to treat macular degeneration (bevacizumab). Thus, long-term use with biological compounds can be effective and safe. Consistent with therapeutic approaches comprising the administration of a biological compound such as an antibody is the fact that antibodies are readily detected in the matrix of dystrophic muscle, such as the muscle of DMD patients.

[0007] A number of approaches, including but not limited to angiotensin inhibition, either through the converting enzyme or the angiotensin receptor, aldosterone inhibition, and inhibition by antibodies directed against TGF.beta. have been or are being tested to reduce fibrosis in DMD. [Cohn et al., Nat Med. 13: 204-10 (2007); Rafael-Fortney et al., Circulation. 124: 582-8 (2011); Nelson et al., Am J Pathol. 178: 2611-21 (2011)]. A major limitation of these approaches is that these drugs are systemically active and often have unwanted effects such as reduced blood pressure. Given the relative hypotension of DMD patients, especially advanced DMD patients, such approaches are limited.

SUMMARY

[0008] Disclosed herein are compositions and methods for treating a transforming growth factor beta superfamily protein-related disease. Compositions according to the disclosure modulate the activity and/or proteolysis of latent TGF.beta. binding protein 4 (LTBP4). Methods according to the disclosure comprise administration of an effective amount of a modulator of LTBP4, with that effective amount being an amount sufficient to prevent, delay onset and/or treat a disorder according to the disclosure. The compositions and methods provided by the disclosure will improve one or more symptoms associated with disorders according to the disclosure in afflicted individuals, thereby improving their quality of life while alleviating the financial, psychological and physical burdens imposed on modern healthcare systems.

[0009] Accordingly, in one aspect the disclosure provides a method of treating a patient having a transforming growth factor beta (TGF.beta.) superfamily protein-related disease, comprising administering an effective amount of an agent that modulates proteolysis of latent TGF.beta. binding protein 4 (LTBP4) to a patient in need thereof.

[0010] A related aspect of the disclosure provides methods of delaying onset or preventing a transforming growth factor beta (TGF.beta.) superfamily protein-related disease, comprising administering an effective amount of an agent that modulates proteolysis of latent TGF.beta. binding protein 4 (LTBP4) to a patient in need thereof.

[0011] In various embodiments of the foregoing methods, the patient has a disease selected from the group consisting of Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury and colon cancer.

[0012] In further embodiments, the agent is selected from the group consisting of an antibody, an inhibitory nucleic acid and a peptide.

[0013] In further aspects of the disclosure, the methods disclosed herein further comprise administering an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.

[0014] Another aspect of the disclosure is drawn to a method of treating a patient having a transforming growth factor beta (TGF.beta.)-related disease, comprising administering to the patient an effective amount of an agent that upregulates the activity of latent TGF.beta. binding protein 4 (LTBP4).

[0015] A further aspect of the disclosure provides a method of delaying onset or preventing a transforming growth factor beta (TGF.beta.)-related disease, comprising administering to the patient an effective amount of an agent that upregulates the activity of latent TGF.beta. binding protein 4 (LTBP4).

[0016] In some embodiments of the methods, LTBP4 interacts with a TGF.beta. superfamily protein, and in still further embodiments the TGF.beta. superfamily protein is selected from the group consisting of TGF.beta., a growth and differentiation factor (GDF), activin, inhibin, and a bone morphogenetic protein. In specific embodiments, the GDF is myostatin.

[0017] In additional embodiments, the agent is selected from the group consisting of a peptide, an antibody and a polynucleotide capable of expressing a protein having LTBP4 activity, each as disclosed herein. In some embodiments, the polynucleotide is contained in a vector and in further embodiments the vector is a viral vector. The disclosure further contemplates embodiments wherein the viral vector is selected from the group consisting of a herpes virus vector, an adeno-associated virus (AAV) vector, an adeno virus vector, and a lentiviral vector. In one embodiment, the AAV vector is recombinant AAV9.

[0018] In some embodiments, the compositions and methods disclosed herein are for treating a transforming growth factor beta-related disease in a patient. In particular embodiments, the patient suffers from a disease selected from the group consisting of Duchenne Muscular Dystrophy (DMD), Limb Girdle Muscular Dystrophy (LGMD), Becker Muscular Dystrophy (BMD), myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury and colon cancer.

[0019] An additional aspect of the disclosure is drawn to methods as disclosed above that further comprise administering a therapeutically effective amount of a second agent that is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.

[0020] In some embodiments, an isolated antibody is provided that specifically binds to a peptide comprising any one of the sequences set forth in SEQ ID NOs: 2-5. In further embodiments, the disclosure provides an isolated antibody that specifically binds to a peptide that is at least 70% identical to a peptide comprising any one of the sequences set forth in SEQ ID NOs: 2-5, wherein the antibody retains an ability to specifically bind to LTBP4 and to decrease the susceptibility of LTBP4 to proteolysis.

[0021] Still further embodiments of the disclosure provide a peptide comprising the sequence as set out in SEQ ID NOs: 2-5, or a peptide that is at least 70% identical to any one of the sequences as set out in SEQ ID NO: 2-5 that retains an ability to act as a substrate for a protease.

[0022] In another aspect, a pharmaceutical formulation is provided comprising an effective amount, such as a therapeutically effective amount, of an antibody and/or peptide of the disclosure, and a pharmaceutically acceptable carrier or diluent.

[0023] A further aspect of the disclosure provides a kit comprising an effective amount, such as a therapeutically effective amount, of an antibody and/or peptide of the disclosure, a pharmaceutically acceptable carrier or diluent and instructions for use.

[0024] In some embodiments, the formulation or the kit of the disclosure further comprises an effective amount, such as a therapeutically effective amount, of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.

[0025] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, because various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 depicts a model for action of LTBP4 (latent TGF.beta. binding protein 4). LTBP4 binds directly to TGF.beta. family member proteins. In the extracellular matrix, the complex of LTBP4 protein and TGF.beta. forms the large latent complex. With proteolysis, LTBP4 undergoes a conformational change which releases TGF.beta., thereby making it available for release and binding TGF.beta. receptors on neighboring cells. TGF.beta. binding to its receptor results in TGF.beta. signaling in cells.

[0027] FIG. 2 depicts the gene structure of LTBP4. An insertion deletion polymorphism in Ltbp4 alters the proline-rich region in mice. The N-terminus of LTBP binds the extracellular matrix (ECM). The LTBP4 protein is composed of multiple epidermal growth factor (EGF) repeats interspersed with motifs containing 8 cysteine residues (8-Cys). The third 8-cys repeat binds TGF.beta. directly. The proline-rich region (labeled horizontal rectangle) separates the matrix-binding domain from the remainder of the protein. Mouse129 is protected against muscular dystrophy because of insertion of 12 amino acids in the proline-rich region. Muscular dystrophy in D2 strains of mice is more severe. Rat, dog, cow, and humans each harbor a larger deletion of the proline-rich region of LTBP4.

[0028] FIG. 3 depicts results of studies using fragments of human and mouse LTBP4 that were expressed and digested. Human LTBP4 is more readily cleaved than murine LTBP4. The amino acid positions indicated for TP and TP2E are based on the human isoform a LTBP4 sequence (SEQ ID NO: 1).

[0029] FIG. 4 depicts results of studies using a blocking antibody that was designed to recognize and bind the proline-rich region (Y) of LTBP4. When incubated with cell lysates expressing LTBP4, the presence of the antibody inhibits cleavage by plasmin. A nonspecific antibody did not inhibit cleavage.

[0030] FIG. 5 depicts that the proline-rich region of human LTBP4 is more easily cleaved than murine LTBP4.

[0031] FIG. 6 shows results of a study using a blocking antibody that inhibited cleavage of full-length LTBP4. A nonspecific blocking antibody showed no effect. Assays were conducted in triplicate with significant inhibition of proteolysis observed.

[0032] FIG. 7 shows results of a study wherein a bacterial artificial transgene expressing human LTBP4 (hLTBP4 Tg) was crossed into the mouse mdx model of Duchenne Muscular Dystrophy. (A) hLTBP4/mdx mice have enhanced fibrosis in their muscles as determined grossly through histology and by direct quantitation. When quantified, fibrotic area was increased in hLTBP4/mdx mice compared to littermate mdx mice. (B) hLTBP4/mdx mice have reduced grip strength. Grip strength was compared between hLTBP4/mdx mice and mdx mice to determine whether the human LTBP4 gene worsens the muscle disease seen in mdx mice. hLTBP4/mdx mice are weaker than mdx littermates (*). Grip strength was measured using the Treat NMD standard protocols.

[0033] FIG. 8 shows that LTBP4 forms a complex with myostatin. HEK293 cells were transfected with LTBP4 and epitope-tagged myostatin. LTBP4 was precipitated with two different anti-LTBP4 antibodies (lanes 3 and 5), and the precipitate was then immunoblotted with anti-myc antibody. Unprocessed myostatin was detected in the immunoprecipitate (arrow). The upper band in lanes 1 and 2 that migrates above 50 KDa is endogenous c-myc, which is 63 KDa.

[0034] FIG. 9 depicts the results of experiments testing the effects of cardiotoxin on both wild-type mice and transgenic mice that express human LTBP4. A) transgenic mice displayed enhanced injury after cardiotoxin injury seen as greater inflammatory mononuclear cell infiltrate and fibrosis and fat deposition into the injured muscle. B) LTBP4 protein levels are increased after injury.

[0035] FIG. 10 shows that anti-LTBP4 antibodies mitigate muscle injury in vivo. Compared to PBS-injected mice, LTBP4-831 antibody-treated mice showed reduced central nucleation (panel A) and reduced fibrosis (panel B) following cardiotoxin injection.

[0036] FIG. 11 shows that increased TGF.beta. signaling is associated with increased macrophage infiltration in hLTBP4/mdx muscle compared to mdx muscle. A) Muscles were stained with antibodies to activated macrophages using the F4/80 antibody. B) hLTBP4/mdx muscle shows an increase in cleaved LTBP4 protein compared to mdx, while little LTBP4 protein is seen in wild type and hLTBP4 muscle in the absence of injury or muscular dystrophy. C) Proteolytic cleavage and a conformational change in LTBP4 is associated with TGF.beta. release.

DETAILED DESCRIPTION

[0037] The transforming growth factor beta (TGF.beta.) superfamily consists of more than 40 members including TGF.beta., activins, inhibins, growth differentiation factors and bone morphogenetic proteins (BMPs). All members of this family share common sequence elements and structural motifs. They are multifunctional regulators of cell division, differentiation, migration, adhesion, organization and death, promoting extracellular matrix (ECM) production, tissue homeostasis and embryogenesis [Massague et al., Genes Dev 19: 2783-810 (2005); Javelaud et al., Int J Biochem Cell Biol 36: 1161-5 (2004); Moustakas et al., Immunol Lett 82: 85-91 (2002)]. Among these proteins, TGF.beta. has a crucial role in tissue homeostasis and the disruption of the TGF.beta. pathway has been implicated in many human diseases, including cancer, autoimmune, fibrotic, and cardiovascular diseases [Ruiz-Ortega et al., Cardiovascular Research 74: 196-206 (2007)].

[0038] TGF.beta. is synthesized as an inactive protein, named latent TGF.beta., which consists of a main region and a latency associated peptide (LAP). This protein interacts with the latent TGF.beta. binding proteins (e.g., LTBP4) and is anchored in the extracellular matrix (ECM). TGF.beta. is activated following proteolysis of LTBP4, which results in release of TGF.beta.. Specifically, and as disclosed herein, the proline-rich region of LTBP4 is susceptible to proteolysis by a protease, and this proteolysis leads to release and activation of TGF.beta..

[0039] Active TGF.beta. then binds its receptors and functions in autocrine and paracrine manners to exert its biological and pathological activities via Smad-dependent and independent signaling pathways [Lan, Int J Biol Sci 7(7): 1056-1067 (2011); Derynck et al., Nature. 425: 577-84 (2003)].

[0040] Thus, inhibition of the proteolysis of LTBP4 will inhibit the release of bound TGF.beta., and the resulting sequestration of TGF.beta. will inhibit the downstream signaling effects of TGF.beta., resulting in mitigation of TGF.beta.-related disease.

[0041] The working examples and experimental data disclosed therein demonstrate that the proline-rich region of LTBP4 is susceptible to proteolysis. These results support therapeutics and therapies directed to modulating the proteolysis of LTBP4 in a patient having a TGF.beta.-related disease.

[0042] The experimental results disclosed herein also demonstrate that proteolysis of LTBP4 can be inhibited by antibodies. Inhibition of LTBP4 proteolysis using pharmacological approaches is expected to provide an effective approach to the treatment of TGF.beta.-related diseases.

[0043] Experimental results disclosed herein additionally demonstrate that a fragment of human LTBP4 is more susceptible to proteolysis than the mouse LTBP4 sequence. Consequently, a phenomenon elucidated in the mouse is mirrored in humans, and inhibition of LTPB4 proteolysis is expected to provide an effective treatment for TGF.beta.-related diseases.

[0044] Unless otherwise defined herein, scientific and technical terms employed in the disclosure shall have the meanings that are commonly understood and used by one of ordinary skill in the art. Unless otherwise required by context, it will be understood that singular terms shall include plural forms of the same and plural terms shall include the singular. Specifically, as used herein and in the claims, the singular forms "a" and "an" include the plural reference unless the context clearly indicates otherwise.

[0045] As used in the disclosure, the term "treating" or "treatment" refers to an intervention performed with the intention of preventing the further development of or altering the pathology of a disease or infection. Accordingly, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Of course, when "treatment" is used in conjunction with a form of the separate term "prophylaxis," it is understood that "treatment" refers to the narrower meaning of altering the pathology of a disease or condition. "Preventing" refers to a preventative measure taken with a subject not having a condition or disease. A therapeutic agent may directly decrease the pathology of a disease, or render the disease more susceptible to treatment by another therapeutic agent(s) or, for example, the host's immune system. Treatment of patients suffering from clinical, biochemical, or subjective symptoms of a disease may include alleviating one or more of such symptoms or reducing the predisposition to the disease. Improvement after treatment may be manifested as a decrease or elimination of one or more of such symptoms.

[0046] As used herein, the phrase "effective amount" is meant to refer to an amount of a therapeutic (i.e., a therapeutically effective amount), prophylactic (i.e., a prophylactically effective amount), or symptom-mitigating (i.e., a symptom-mitigating effective amount) compound (e.g., agent or second agent) sufficient to modulate proteolysis of latent TGF.beta. binding protein 4 (LTBP4), such as would be appropriate for an embodiment of the disclosure in eliciting the desired therapeutic, prophylactic, or symptom-mitigating effect or response, including alleviating one or more of such symptoms of disease or reducing the predisposition to the disease.

[0047] As used herein, "hybridization" means the pairing of substantially complementary strands of polymeric compounds. One mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleotide bases (nucleotides) of the strands of polymeric compounds. For example, adenine and thymine are complementary nucleotides which pair through the formation of hydrogen bonds. Hybridization can occur under varying circumstances.

[0048] An antisense compound is "specifically hybridizable" when binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause a modulation of function and/or activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target nucleic acid sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo applications such as therapeutic treatment, and under conditions in which assays are performed in the case of in vitro assays.

[0049] As used herein, the phrase "stringent hybridization conditions" or "stringent conditions" refers to conditions under which a compound (e.g., agent) disclosed herein will hybridize to its target sequence, but to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances and in the context of this disclosure, "stringent conditions" under which polymeric compounds hybridize to a target sequence are determined by the nature and composition of the polymeric compounds and by the application(s) involved. In general, stringent hybridization conditions comprise low concentrations (<0.15M) of salts with inorganic cations such as Na.sup.++ or K.sup.++ (i.e., low ionic strength), temperatures higher than 20.degree. C.-25.degree. C. below the T.sub.m of the polymeric compound:target sequence complex, and the presence of denaturants such as formamide, dimethylformamide, dimethyl sulfoxide, or the detergent sodium dodecyl sulfate (SDS). An example of a set of high stringency hybridization conditions is 0.1X sodium chloride-sodium citrate buffer (SSC)/0.1% (w/v) SDS at 60.degree. C. for 30 minutes.

[0050] "Complementary," as used herein, refers to the capacity for precise pairing between two nucleotides on one or two polymeric strands. Consistent with Watson-Crick base pairing rules (A binds T or U; G binds C; where A, G, C, T and U are the conventional ribo-, or deoxyribo-, nucleotide monophosphates). "Specifically hybridizable" and "complementary" are terms which are used to indicate a sufficient degree of precise nucleotide pairing or complementarity over a sufficient number of nucleotides such that stable and specific binding occurs between the polymeric compound and a target nucleic acid. The terms thus allow for base pairing gaps, but not to the extent that it prevents stable and specific binding.

[0051] It is understood in the art that the sequence of a polymeric compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. Moreover, a polynucleotide may hybridize over one or more segments such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure). The polymeric compounds of the present disclosure comprise at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% sequence complementarity to a target region, within the target nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleotides of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleotides may be clustered or interspersed with complementary nucleotides and need not be contiguous to each other or to complementary nucleotides. As such, an antisense compound which is 18 nucleotides in length having 4 (four) noncomplementary nucleotides which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present disclosure. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined by use of routine sequence comparison software and algorithms, e.g., BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art [Altschul et al., J. Mol. Biol., 215: 403-410 (1990); Zhang and Madden, Genome Res., 7: 649-656 (1997)]. Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman [Adv. Appl. Math., 2: 482-489 (1981)].

[0052] As used herein, the term "(T.sub.m)" means melting temperature and refers to the temperature, under defined ionic strength, pH, and nucleic add concentration, at which 50% of the polynucleotides complementary to the target sequence hybridize to the target sequence at equilibrium. Typically, stringent conditions will be those in which the salt concentration is at least about 0.01 to 1.0 M sodium ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30.degree. C. for short polynucleotides (e.g., 10 to 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide.

[0053] As used herein, "modulation" of an activity means either an increase (stimulation) or a decrease (inhibition) in that activity. For example, and without limitation, a modulation of proteolysis can mean either an increase in proteolysis or a decrease in proteolysis.

Latent TGF.beta. Binding Protein 4 (LTBP4)

[0054] The present disclosure is directed in part to Ltbp4, the gene encoding latent TGF.beta. binding protein (LTBP4; GenBank Accession Number NP_001036009.1; SEQ ID NO: 1), which was identified in a genetic screen as a major genetic modifier of muscular dystrophy [Heydemann et al., J Clin Invest. 119: 3703-12 (2009)]. This genetic screen was conducted using mice lacking the dystrophin-associated protein, .gamma.-sarcoglycan (Sgcg null mice). The Sgcg model of limb girdle muscular dystrophy (LGMD) was selected because there was ample evidence from human LGMD of the importance of genetic modifiers affecting the severity of this disease [McNally et al., Am J Hum Genet. 59:1040-7 (1996)]. It was surprisingly found that modifiers identified for sarcoglycan-mediated muscular dystrophy similarly modify DMD. Disruption of the dystrophin glycoprotein complex, either in DMD or the sarcoglycan-associated LGMDs, leads to a fragile muscle membrane, enhanced myofiber breakdown, and replacement of normal muscle tissue by fibrosis. Early in pathology, fibrotic replacement is minimal, but in the advanced DMD patient, the muscle is nearly completely replaced by fibrosis.

[0055] LTBP4 is located on human chromosome 19q13.1-q13.2, and is an extracellular matrix protein that binds and sequesters TGF.beta. (FIG. 1). LTBP4 modifies murine muscular dystrophy through a polymorphism in the Ltbp4 gene. There are two common variants of the Ltbp4 gene in mice. Most strains of mice, including the mdx mouse, have the Ltbp4 insertion allele (Ltbp4.sup.I/I). Insertion of 36 base pairs (12 amino acids) into the proline-rich region of LTBP4 encoded by Ltbp4.sup.I/I leads to milder disease. Deletion of 36 bp/12aa in the proline-rich region is associated with more severe disease (Ltbp4.sup.D/D) (FIG. 2). It was found that the Ltbp4 genotype correlated strongly with two different aspects of muscular dystrophy pathology, i.e., membrane leakage and fibrosis, and these features define DMD pathology.

[0056] To assess muscle membrane leakage, Evans blue dye (EBD), which can complex with serum albumin, and thus is a measure of membrane permeability, was used. EBD is injected intraperitoneally and muscles from the injected animals are harvested approximately 8-40 hours later. Muscle membrane leakage was assessed by determining the amount of EBD in multiple different muscle groups, including quadriceps and other skeletal muscles. Hydroxyproline content was measured to quantify fibrosis, and this assay was also performed on multiple different muscle groups. The Ltbp4 genotype was found to account for nearly 40% of the variance in membrane leakage in quadriceps muscle [Swaggart et al., Physiol Genomics 43: 24-31 (2011)]. Similarly, the Ltbp4 genotype also highly correlated with fibrosis in limb-based skeletal muscles where it also accounted for a significant amount of the variance. Ltbp4 is an unusually strong genetic modifier and acts both on membrane fragility as well as fibrosis. Accordingly, the present disclosure identifies LTBP4 as a target for therapy because it will stabilize the plasma membrane in addition to reducing fibrosis in patients in need thereof.

[0057] As discussed hereinabove, LTBP4 is a matrix-associated protein that binds and sequesters TGF.beta.. TGF.beta. in this form is the large latent complex, which requires further proteolysis to become fully active. It is expected that matrix-bound latent TGF.beta. is the least active form with regard to receptor engagement, and therefore represents an ideal step at which to inhibit TGF.beta. release. LTBP4, the fourth member of the LTBP carrier protein family, is highly expressed in heart, muscle, lung and colon [Saharinen et al., J Biol Chem. 273: 18459-69 (1998)]. LTBP4 protein, like other members of this family, can be proteolyzed with plasmin, which results in TGF.beta. release [Saharinen et al., J Biol Chem. 273: 18459-69 (1998); Ge et al., J Cell Biol. 175: 111-20 (2006)]. The 12-amino-acid insertion/deletion alters the susceptibility of LTBP4 to proteolysis, which in turn alters TGF.beta. release and its ability to bind TGF.beta. receptors and activate signaling. It is disclosed herein that inhibiting LTBP4 cleavage will hold TGF.beta. inactive and limit the downstream effects of TGF.beta. release.

Agents

[0058] Methods of the disclosure contemplate treating a patient having a TGF.beta.-related disease comprising administering to the patient an effective amount of an agent that modulates proteolysis of LTBP4.

[0059] The term "agent" in this context refers to an antibody, an inhibitory nucleic acid, a peptide, and combinations thereof.

Antibodies

[0060] The term "antibody" is used in the broadest sense and includes fully assembled antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody fragments that can bind antigen (e.g., Fab', F'(ab).sub.2, Fv, single chain antibodies, diabodies), camel bodies and recombinant peptides comprising the foregoing provided they exhibit the desired biological activity. Antibody fragments may be produced using recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies and are described further below. Non-limiting examples of monoclonal antibodies include murine, chimeric, humanized, human, and human-engineered immunoglobulins, antibodies, chimeric fusion proteins having sequences derived from immunoglobulins, or muteins or derivatives thereof, each described further below. Multimers or aggregates of intact molecules and/or fragments, including chemically derivatized antibodies, are contemplated. Antibodies of any isotype class or subclass are contemplated.

[0061] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to conventional (polyclonal) antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized in a homogeneous culture, uncontaminated by other immunoglobulins with different specificities and characteristics.

[0062] The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the disclosure may be made by the hybridoma method first described by Kohler et al., Nature 256: 495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567, incorporated herein by reference). The "monoclonal antibodies" may also be recombinant, chimeric, humanized, human, Human Engineered.TM., or antibody fragments, for example.

[0063] Antibodies described herein are discussed in Example 3. In certain embodiments, a variant of an antibody of the disclosure is contemplated. By "variant" is meant an antibody comprising one or more amino acid substitutions, amino acid deletions, or amino acid additions to a reference amino acid sequence. Variants include, but are not limited to, antibodies having an amino acid sequence that is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the amino acid sequences of an antibody provided herein, provided that the antibody variant retains the ability to block and/or inhibit the proteolysis of LTBP4.

[0064] In further embodiments, an anti-LTBP4 antibody described herein specifically binds at least one peptide selected from the group consisting of peptides having a sequence set forth in SEQ ID NOs: 2-5, or a peptide selected from the group consisting of peptides having a sequence at least 70% identical to a peptide having a sequence set forth in SEQ ID NOs: 2-5. In additional embodiments, an anti-LTBP4 antibody described herein binds at least one epitope of LTBP4 with an affinity of 10.sup.-6 M, 10.sup.-7 M, 10.sup.-8 M, 10.sup.-9 M, 10.sup.-10 M, 10.sup.-11 M, or 10.sup.-12 M or less (lower meaning higher binding affinity), or optionally binds all of LTBP4 with an affinity of 10.sup.-6 M, 10.sup.-7 M, 10.sup.-8 M, 10.sup.-9 M 10.sup.-10 M, 10.sup.-11 M, or 10.sup.-12 M or less. In other embodiments, an antibody described herein "specifically binds" to LTBP4 with at least 2-50 fold, 10-100 fold, 2-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold, or 20-50%, 50-100%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% higher affinity compared to binding to a non-target protein.

[0065] Antibodies described hereinbelow are suitable for use in the methods described herein. Additional antibodies are also contemplated, provided the antibody possesses the property of modulating the proteolysis or upregulating the activity of LTBP4. Such antibodies may, for example, be humanized according to known techniques and modified and/or formulated to allow delivery and intracellular contact with LTBP4.

Peptides

[0066] The disclosure provides peptides that have the ability to act as a substrate for a protease (i.e., "a protease-substrate peptide"). The protease, as discussed herein, means a protease that can cleave LTBP4. In one embodiment, the protease is a serine protease. In further embodiments, the protease is selected from the group consisting of plasmin, leukocyte elastase, pancreatic elastase, human mast cell chymase, trypsin, chymotrypsin, pepsin and papain.

[0067] The ability of a peptide to act as a substrate for a protease can be readily determined by one of ordinary skill in the art. By way of non-limiting example, a peptide can be tested in vitro by incubating a labeled LTBP4 protein (or a labeled fragment thereof) with a candidate peptide and a serine protease. The label can be any detectable label known in the art, and in one embodiment is a radioactive label. Following incubation and subsequent gel electrophoresis, it can be determined whether the LTBP4 protein (or fragment thereof) was refractory to proteolysis based on the size of the protein on the gel. If the LTBP4 protein was not protected from proteolysis by the peptide, the radioactive band on the gel will be smaller than one would expect for a full-length LTBP4 protein. Thus, while peptide sequences disclosed herein are contemplated for use according to the methods of the disclosure, additional peptides are also contemplated, with the proviso being their ability to act as a substrate for a protease in a manner that renders them an inhibitor of LTBP4 proteolysis.

[0068] Use of one or more peptides or antibodies of the disclosure, each of which has an ability to act either as a substrate for a protease (peptide) or to act as an inhibitor of proteolysis (antibody), is expected to upregulate the activity of LTBP4 compared to the activity of LTBP4 in the absence of the one or more peptides. In this context, upregulation of LTBP4 activity results from its protection from proteolysis via the action of the one or more peptides and/or antibodies of the disclosure. The downstream effect of this upregulation of LTBP4 activity is the concomitant downregulation of TGF.beta. signaling. Intact LTBP4 will continue to bind and sequester TGF.beta. and thus prevent its release and subsequent downstream effects. Thus, in various embodiments, the upregulation of LTBP4 activity is measured by quantitating TGF.beta. signaling. Methods of quantitating TGF.beta. signaling are known to those of skill in the art, and include determination of Smad signaling from a biological sample obtained from a patient. It is contemplated that, in some embodiments, Smad signaling in a patient being administered one or more agent(s) and/or additional agent(s) of the disclosure is reduced by at least about 1% and up to about 5%, about 10%, about 20%, about 30%, about 40% or about 50% relative to a patient not so treated. In further embodiments, Smad signaling in a patient being administered one or more agent(s) and/or additional agent(s) of the disclosure is reduced by at least about 10% and up to about 20%, about 50%, about 70%, about 80%, about 90%, about 99% or more relative to a patient not so treated. In specific embodiments, Smad signaling in a patient being administered one or more agent(s) and/or additional agent(s) of the disclosure is reduced by at least about 1%, about 2%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more relative to a patient not so treated.

[0069] Peptides described above (i.e., peptide inhibitors of LTBP4 proteolysis) are set forth in Example 3 and Table 1. Thus, in certain embodiments, the peptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 2-5 or a variant of any of the foregoing. By "variant" is meant a peptide comprising one or more amino acid substitutions, amino acid deletions, or amino acid additions to a reference amino acid sequence (e.g., any one of SEQ ID NOs: 2-5). Variants include, but are not limited to, peptides having an amino acid sequence that is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the amino acid sequences provided herein while retaining the ability to act as a substrate for a protease.

[0070] In one aspect, the peptide consists of 35 amino acids or less. In various embodiments, the peptide comprises 15-35 amino acid residues (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acid residues). It is also contemplated that a peptide described herein comprising one or more deletions is suitable in the context of the disclosure so long as the peptide can act as a substrate for a protease. In some embodiments, amino acids are removed from within the amino acid sequence, at the N-terminus, and/or at the C-terminus. Such peptide fragments can comprise 3-14 amino acid residues (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 amino acid residues).

[0071] Optionally, the peptide comprises one or more amino acid substitutions (with reference to any of the amino acid sequences provided herein) that do not destroy the ability of the peptide to act as a substrate for a protease. Amino acid substitutions include, but are not limited to, those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinities, and/or (4) confer or modify other physiochemical or functional properties on a peptide. In one aspect, the substitution is a conservative substitution, wherein an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art, and include amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid and glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, and cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan), beta-branched side chains (e.g., threonine, valine, and isoleucine) and side chains with aromatic character (e.g., tyrosine, phenylalanine, tryptophan, and histidine). It will be appreciated, however, that a practitioner is not limited to conservative substitutions, so long as the resulting peptide retains the ability to act as a substrate, in whole or in part, for a protease. The disclosure also embraces protease-substrate peptides comprising atypical, non-naturally occurring amino acids, which are well known in the art. The individual amino acids may have either L or D stereochemistry when appropriate, although the L stereochemistry is typically employed for all of the amino acids in the peptide.

[0072] The disclosure further includes protease-substrate peptide variants comprising one or more amino acids inserted within an amino acid sequence provided herein and/or attached to the N-terminus or C-terminus. In some embodiments, the peptide further comprises one or more amino acids that facilitate synthesis, handling, or use of the peptide including, but not limited to, one or two lysines at the N-terminus and/or C-terminus to increase solubility of the peptide. Suitable fusion proteins include, but are not limited to, proteins comprising a peptide linked to another polypeptide, a polypeptide fragment, or amino acids not generally recognized to be part of the protein sequence. In some embodiments, a fusion peptide comprises the entire amino acid sequences of two or more peptides or, alternatively, comprises portions (fragments) of two or more peptides. In addition to all or part of the peptides described herein, a fusion protein optionally includes all or part of any suitable peptide comprising a desired biological activity/function. Indeed, in some embodiments, a peptide is operably linked to, for instance, one or more of the following: a peptide with long circulating half-life, a marker protein, a peptide that facilitates purification of the protease-substrate peptide, a peptide sequence that promotes formation of multimeric proteins, or a fragment of any of the foregoing. In one embodiment, two or more protease-substrate peptides are fused together, linked by a multimerization domain, or attached via chemical linkage to generate a protease-substrate peptide complex. The protease-substrate peptides may be the same or different.

[0073] "Derivatives" are also contemplated by the disclosure and include protease-substrate peptides that have been chemically modified in some manner distinct from addition, deletion, or substitution of amino acids. In this regard, a peptide provided herein is chemically bonded with polymers, lipids, other organic moieties, and/or inorganic moieties. Derivatives are prepared in some situations to increase solubility, absorption, or circulating half-life. Various chemical modifications eliminate or attenuate any undesirable side effect of the agent. In this regard, the disclosure provides protease-substrate peptides covalently modified to include one or more water-soluble polymer attachments. Useful polymers known in the art include, but are not limited to, polyethylene glycol, polyoxyethylene glycol, polypropylene glycol, monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of any of the foregoing. For further discussion of water soluble polymer attachments, see U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; and 4,179,337, incorporated herein by reference. In other embodiments, a peptide derivative includes a targeting moiety specific for a particular cell type, tissue, and/or organ. Alternatively, the peptide is linked to one or more chemical moieties that facilitate purification, detection, multimerization, and/or characterization of peptide activity.

[0074] Derivatives also include peptides comprising modified or non-proteinogenic amino acids or a modified linker group [see, e.g., Grant, Synthetic Peptides: A User's Guide, Oxford University Press (1992)]. Modified amino acids include, for example, amino acids wherein the amino and/or carboxyl group is replaced by another group. Non-limiting examples include modified amino acids incorporating thioamides, ureas, thioureas, acylhydrazides, esters, olefines, sulfonamides, phosphoric acid amides, ketones, alcohols, boronic acid amides, benzodiazepines and other aromatic or non-aromatic heterocycles [see Estiarte et al., Burgers Medicinal Chemistry, 6th edition, Volume 1, Part 4, John Wiley & Sons, New York (2002)]. Modified amino acids are often connected to the peptide with at least one of the above-mentioned functional groups instead of an amide bond. Non-proteinogenic amino acids include, but are not limited, to .beta.-alanine (.beta.-Ala), norvaline (Nva), norleucine (Nle), 4-aminobutyric acid (.gamma.-Abu), 2-aminoisobutyric acid (Aib), 6-aminohexanoic acid (.epsilon.-Ahx), ornithine (orn), hydroxyproline (Hyp), sarcosine, citrulline, cysteic acid (Coh), cyclohexylalanine, methioninesulfoxide (Meo), methioninesulfone (Moo), homoserinemethylester (Hsm), propargylglycine (Eag), 5-fluorotryptophan (5Fw), 6-fluorotryptophan (6Fw), 3',4'-dimethoxyphenyl-alanine (Ear), 3',4'-difluorophenylalanine (Dff), 4'-fluorophenyl-alanine (Pff), 1-naphthyl-alanine (1Ni), 1-methyltryptophan (1Mw), penicillamine (Pen), homoserine (HSe), .alpha.-amino isobutyric acid, t-butylglycine, t-butylalanine, phenylglycine (Phg), benzothienylalanine (Bta), L-homo-cysteine (L-Hcys), N-methyl-phenylalanine (NMF), 2-thienylalanine (Thi), 3,3-diphenylalanine (Ebw), homophenylalanine (Hfe), s-benzyl-L-cysteine (Ece) and cyclohexylalanine (Cha). These and other non-proteinogenic amino acids may exist as D- or L-isomers and D-isomers of proteinogenic amino acids may also be found in derivatives.

[0075] Examples of modified linkers include, but are not limited to, the flexible linker 4,7,10-trioxa-1,13-tridecanediamine (Ttds), glycine, 6-aminohexanoic acid, beta-alanine, and combinations of Ttds, glycine, 6-aminohexanoic acid and beta-alanine.

[0076] Protease-substrate peptides are made in a variety of ways. In some embodiments, the peptides are synthesized by solid-phase synthesis techniques including those described in Merrifield, J. Am. Chem. Soc. 85: 2149 (1963); Davis et al., Biochem. Intl. 10: 394-414 (1985); Larsen et al., J. Am. Chem. Soc. 115: 6247 (1993); Smith et al., J. Peptide Protein Res. 44:183 (1994); O'Donnell et al., J. Am. Chem. Soc. 118: 6070 (1996); Stewart and Young, Solid Phase Peptide Synthesis, Freeman (1969); Finn et al., The Proteins, 3rd ed., vol. 2, pp. 105-253 (1976); and Erickson et al., The Proteins, 3rd ed., vol. 2, pp. 257-527 (1976). Alternatively, the protease-substrate peptide is expressed recombinantly by introducing a nucleic acid encoding a protease-substrate peptide into host cells that are cultured to express the peptide. Such peptides are purified from the cell culture using standard protein purification techniques.

[0077] The disclosure also encompasses a nucleic acid comprising a nucleic acid sequence encoding an antibody or protease-substrate peptide. Methods of preparing DNA and/or RNA molecules are well known in the art. In one aspect, a DNA/RNA molecule encoding an antibody or protease-substrate peptide provided herein is generated using chemical synthesis techniques and/or using polymerase chain reaction (PCR). If desired, an antibody and/or protease-substrate peptide coding sequence is incorporated into an expression vector. One of ordinary skill in the art will appreciate that any of a number of expression vectors known in the art are suitable in the context of the disclosure, such as, but not limited to, plasmids, plasmid-liposome complexes, and viral vectors. Any of these expression vectors are prepared using standard recombinant DNA techniques described in, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 2d edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994). Optionally, the nucleic acid is operably linked to one or more regulatory sequences, such as a promoter, activator, enhancer, cap signal, polyadenylation signal, or other signal involved in the control of transcription or translation.

[0078] As with all binding agents and binding assays, one of skill in this art recognizes that the various moieties to which a binding agent should not detectably bind in order to be biologically (e.g., therapeutically) effective would be exhaustive and impractical to list. Therefore, when discussing a peptide, the term "specifically binds" refers to the ability of a peptide to bind (or otherwise inhibit) a protease involved in cleavage of LTBP4 with greater affinity than it binds to a non-target control protein that is not the protease. For example, the peptide may bind to the protease with an affinity that is at least, 5, 10, 15, 25, 50, 100, 250, 500, 1000, or 10,000 times greater than the affinity for a control protein. In some embodiments, the peptide binds the protease with greater affinity than it binds to an "anti-target," a protein or other naturally occurring substance in humans wherein binding of the peptide might lead to adverse effects. Several classes of peptides are potential anti-targets. Because protease-substrate peptides are expected to exert their activity in the extracellular matrix, ECM proteins are contemplated as anti-targets.

[0079] Also specifically contemplated by the disclosure are peptides that elicit an immune response to LTBP4 in methods to modulate LTBP4 that involve the host immune system. Thus, in some aspects, a composition is provided that comprises a peptide of the disclosure for use as a vaccine in an individual. Vaccines often include an adjuvant. The compositions comprising one or more peptides described herein may also contain an adjuvant, or be administered with an adjuvant. Thus, the adjuvant may be administered with the peptide compositions or as part of the peptide compositions, before the peptide compositions, or after the peptide compositions.

[0080] A variety of adjuvants are suitable for use in combination with the peptide composition to elicit an immune response to the peptide. Preferred adjuvants augment the intrinsic response to an antigen without causing conformational changes in the antigen that affect the qualitative form of the response. Adjuvants for use in the methods disclosed herein include, but are not limited to, keyhole limpet hemocyanin (KLH), forms of alum (see below) and 3 De-O-acylated monophosphoryl lipid A (MPL or 3-DMP) [see GB 2220211]. Other suitable adjuvant include QS21, which is a triterpene glycoside or saponin isolated from the bark of the Quillaja Saponaria Molina tree found in South America [see Kensil et al., in Vaccine Design: The Subunit and Adjuvant Approach (eds. Powell and Newman, Plenum Press, N Y, 1995); U.S. Pat. No. 5,057,540] and CpG [Bioworld Today, Nov. 15, 1998]. Still other suitable adjuvants are described in the following paragraph.

[0081] One class of suitable adjuvants, noted briefly above, is aluminum salts (alum), such as aluminum hydroxide, aluminum phosphate, and aluminum sulfate. Such adjuvants can be used with or without other specific immunostimulating agents such as MPL or 3-DMP, QS21, polymeric or monomeric amino acids such as polyglutamic acid or polylysine. Another class of suitable adjuvants is oil-in-water emulsion formulations [such as squalene or peanut oil], optionally in combination with immunological stimulants, such as monophosphoryl lipid A [see Stoute et al., N. Engl. J. Med. 336, 86-91 (1997)]. Such adjuvants can be used with or without other specific immunostimulating agents such as muramyl peptides (e.g., N-acetylmuramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanyl-D-isoglutamine (nor-MDP), N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn- -glycero-3-(hydroxyphosphoryloxy)) ethylamide (MTP-PE), N-acetylglucsaminyl-N-acetylmuramyl-L-Al-D-isoglu-L-Ala-dipalmitoxy propylamide (DTP-DPP) Theramide.TM.), or other bacterial cell wall components. Additional oil-in-water emulsions include (a) MF59 (WO 90/14837), containing 5% Squalene, 0.5% Tween 80, and 0.5% Span 85 (optionally containing various amounts of MTP-PE) formulated into submicron particles using a microfluidizer such as a Model 110Y microfluidizer (Microfluidics, Newton Mass.), (b) SAF, containing 10% Squalane, 0.4% Tween 80, 5% pluronic-blocked polymer L121, and thr-MDP, either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion, and (c) the Ribi adjuvant system (RAS), (Ribi Immunochem, Hamilton, Mont.) containing 2% squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphoryl lipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), preferably MPL+CWS (Detox.TM.). Another class of suitable adjuvants is saponin adjuvants, such as Stimulon.TM. (QS21, Aquila, Worcester, Mass.) or particles generated therefrom such as ISCOMs (immunostimulating complexes) and ISCOMATRIX. Other adjuvants include Complete Freund's Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA). Any of the suitable adjuvants may include a cytokine, such as an interleukin (IL-1, IL-2, or IL-12), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), or combinations of cytokines.

[0082] An adjuvant can be administered with a peptide composition of the disclosure as a single composition, or can be administered before, concurrent with or after administration of a peptide composition of the disclosure. Immunogen and adjuvant can be packaged and supplied in the same vial or can be packaged in separate vials and mixed before use. Immunogen and adjuvant are typically packaged with a label indicating the intended application, such as a therapeutic application. If immunogen and adjuvant are packaged separately, the packaging typically includes instructions for mixing before use. The choice of an adjuvant and/or carrier depends on the stability of the vaccine containing the adjuvant, the route of administration, the dosing schedule, the efficacy of the adjuvant for the species being vaccinated, and, in humans, a pharmaceutically acceptable adjuvant is one that has been approved or is approvable for human administration by pertinent regulatory agencies. For example, Complete Freund's adjuvant is not suitable for human administration, while alum, MPL and QS21 are suitable. Optionally, two or more different adjuvants can be used simultaneously, such as alum with MPL, alum with QS21, MPL with QS21, and alum, QS21 and MPL together. Also, Incomplete Freund's adjuvant can be used [Chang et al., Advanced Drug Delivery Reviews 32, 173-186 (1998)], optionally in combination with any of alum, QS21, and MPL and all combinations thereof.

Inhibitory Nucleic Acids

[0083] By "inhibitory nucleic acid" is meant an RNA or DNA polynucleotide that binds to another RNA or DNA (target RNA, DNA). An inhibitory nucleic acid downregulates expression and/or function of a particular target polynucleotide. The definition is meant to include any foreign RNA or DNA molecule which is useful from a therapeutic, diagnostic, or other viewpoint. Such molecules include, for example, antisense polynucleotides such as RNA or DNA molecules, interference RNA (RNAi), micro RNA (miRNA), siRNA, enzymatic RNA, aptamers, ribozymes and other polymeric compounds that hybridize to at least a portion of the target polynucleotide or target polypeptide. As such, these compounds may be introduced in the form of single-stranded, double-stranded, triple-stranded, or partially single-stranded molecules, and the molecules may be linear or circular polymeric compounds.

[0084] The production and use of aptamers is known to those of ordinary skill in the art. In general, aptamers are nucleic acid- or peptide-binding species capable of tightly binding to and discreetly distinguishing target ligands [Yan et al., RNA Biol. 6(3): 316-320 (2009), incorporated by reference herein in its entirety]. Aptamers, in some embodiments, may be obtained by a technique called the systematic evolution of ligands by exponential enrichment (SELEX) process [Tuerk et al., Science 249: 505-10 (1990), U.S. Pat. Nos. 5,270,163, and 5,637,459, each of which is incorporated herein by reference in its entirety]. General discussions of nucleic acid aptamers are found in, for example and without limitation, Nucleic Acid and Peptide Aptamers: Methods and Protocols (Edited by Mayer, Humana Press, 2009) and Crawford et al., Briefings in Functional Genomics and Proteomics 2(1): 72-79 (2003). In various aspects, an aptamer is between 10-100 nucleotides in length.

[0085] As used herein, the term "target polynucleotide" encompasses DNA, RNA (comprising pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA, coding sequences, noncoding sequences, sense polynucleotides or antisense polynucleotides. The specific hybridization of a polymeric compound with its target nucleic acid interferes with the normal function of the target nucleic acid. This modulation of function of a target nucleic acid or polynucleotide by compounds that specifically hybridize to it is generally referred to as antisense modulation or inhibition. The functions of DNA to be interfered include, for example, replication and transcription. The functions of RNA to be interfered include all vital functions such as, for example and without limitation, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, catalytic activity which may be engaged in or facilitated by the RNA, and/or translation to express an encoded polypeptide. The overall effect of such modulation (e.g., inhibition) with target polynucleotide function is modulation of the expression of an encoded product or activity of the polynucleotide itself.

[0086] RNA interference "RNAi" is mediated by double-stranded RNA (dsRNA) molecules that have sequence-specific homology to their target nucleic acid sequence(s) [Caplen et al., Proc. Natl. Acad Sci. USA 98: 9742-9747 (2001)]. In certain embodiments of the present disclosure, the mediators are "small interfering" RNA duplexes (siRNAs) of 5-25 nucleotides. The siRNAs are derived from the processing of dsRNA by an RNase enzyme known as Dicer [Bernstein et al., Nature 409: 363-366 (2001)]. The siRNA duplex products are recruited into a multi-protein siRNA complex termed RISC (RNA-Induced Silencing Complex). Small interfering RNAs that can be used in accordance with the present disclosure can be synthesized and used according to procedures that are well known in the art and that will be familiar to the ordinarily skilled artisan. The siRNAs for use in the methods of the present disclosure suitably comprise between about 1 to about 50 nucleotides (nt). In non-limiting embodiments, siRNAs comprise about 5 to about 40 nt, about 5 to about 30 nt, about 10 to about 30 nt, about 15 to about 25 nt, or about 20-25 nucleotides.

[0087] Methods for inhibiting target polynucleotide expression are provided that include those wherein expression of the target polynucleotide is inhibited by at least about 5% and up to about 10%, 20%, 50% or 100%, at least about 5% and up to about 30%, 60%, 70% or 90%, or at least 10% and up to about 50%, 60%, 70%, 80%, 90% or 100%. In additional embodiments, expression of the target polynucleotide is inhibited by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% compared to target polynucleotide expression in the absence of an inhibitory nucleic acid. In other words, methods of inhibiting the expression or activity of a polynucleotide according to the disclosure result in essentially any degree of inhibition of expression of a target polynucleotide.

[0088] The degree of inhibition is determined in vivo from a body fluid sample or from a biopsy sample or by imaging techniques well known in the art. Alternatively, the degree of inhibition is determined in a cell culture assay, generally as a predictable measure of a degree of inhibition that can be expected in vivo resulting from use of a specific type of specific inhibitory nucleic acid.

Exon Skipping

[0089] Inhibitory nucleic acids are also contemplated for use in exon skipping. In general, exon skipping is a method in which inhibitory nucleic acids are designed to modulate the splicing of a gene of interest, resulting in mRNA transcripts that are able to make some level of gene product with some function. The inhibitory nucleic acids are, in various embodiments, short nucleic acid sequences designed to selectively bind to specific mRNA or pre-mRNA sequences to generate small double-stranded regions of the target mRNA. By binding to these regions and forming double strands at key sites where the spliceosome or proteins of the spliceosome would normally bind, mutated (frameshifting) exons are skipped and the remainder of the pre-mRNA is edited correctly in frame, albeit shorter.

[0090] Exon skipping is generally described in Hoffman et al. [The American J. of Path. 179(1): 12-22 (2010], Lu et al. [The American Soc. of Gene and Cell Therapy 19(1): 9-15 (2011)], and U.S. Pat. Nos. 8,084,601, 7,960,541 and 7,973,015, all of which are incorporated herein by reference in their entireties.

[0091] Thus, the disclosure contemplates that skipping exons that encode the proline-rich region of LTBP4 will generate a protease-resistant protein. In some embodiments, one or more of exons 11, 12 and 13 of mouse LTBP4 (corresponding to exons 11, 12 and 13 in human LTBP4) are targeted for exon skipping. It is expected that skipping of the exons that encode part or all of the proline-rich region of LTBP4 will generate a protein that is resistant to protease activity.

Compositions

[0092] Any of the agents and/or additional agents described herein (or nucleic acids encoding any of the agents and/or additional agents described herein) also is provided in a composition. In this regard, the agent and/or additional agent is formulated with a physiologically-acceptable (i.e., pharmacologically acceptable) carrier, buffer, or diluent, as described further herein. Optionally, the peptide is in the form of a physiologically acceptable salt, which is encompassed by the disclosure. "Physiologically acceptable salts" means any salts that are pharmaceutically acceptable. Some examples of appropriate salts include acetate, trifluoroacetate, hydrochloride, hydrobromide, sulfate, citrate, tartrate, glycolate, and oxalate.

TGF.beta.-Related Diseases

[0093] TGF.beta.-related diseases contemplated for treatment according to the disclosure include Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury, colon cancer, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung diseases, benign prostate hypertrophy, cerebral infarction, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, skin lesions, lymph node fibrosis associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome (MPS); Shigellosis; asthma; adult respiratory distress syndrome; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis including hepatic fibrosis; renal fibrosis, irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Huntington's disease; Parkinson's disease; allergies, including allergic rhinitis and allergic conjunctivitis; cachexia; Reiter's syndrome; acute synoviitis; muscle degeneration, bursitis; tendonitis; tenosynoviitis; osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as osteoporosis or multiple myeloma-related bone disorders; cancer, including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, and non-small cell lung cancer; graft-versus-host reaction; and auto-immune diseases, such as multiple sclerosis, lupus and fibromyalgia; viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus, Severe Acute Respiratory Syndrome (SARS) and cytomegalovirus.

[0094] As used herein, "cardiomyopathy" refers to any disease or dysfunction of the myocardium (heart muscle) in which the heart is abnormally enlarged, thickened and/or stiffened. As a result, the heart muscle's ability to pump blood is usually weakened, often leading to congestive heart failure. The disease or disorder can be, for example, inflammatory, metabolic, toxic, infiltrative, fibrotic, hematological, genetic, or unknown in origin. Such cardiomyopathies may result from a lack of oxygen. Other diseases include those that result from myocardial injury which involves damage to the muscle or the myocardium in the wall of the heart as a result of disease or trauma. Myocardial injury can be attributed to many things such as, but not limited to, cardiomyopathy, myocardial infarction, or congenital heart disease. The cardiac disorder may be pediatric in origin. Cardiomyopathy includes, but is not limited to, cardiomyopathy (dilated, hypertrophic, restrictive, arrhythmogenic, genetic, idiopathic and unclassified cardiomyopathy), sporadic dilated cardiomyopathy, X-linked Dilated Cardiomyopathy (XLDC), acute and chronic heart failure, right heart failure, left heart failure, biventricular heart failure, congenital heart defects, myocardiac fibrosis, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspidal valve stenosis, tricuspidal valve insufficiency, pulmonal valve stenosis, pulmonal valve insufficiency, combined valve defects, myocarditis, acute myocarditis, chronic myocarditis, viral myocarditis, diastolic heart failure, systolic heart failure, diabetic heart failure and accumulation diseases.

TGF.beta. Proteins

[0095] The disclosure provides compositions and methods directed to modulating the activity, including the expression, of LTBP4, which is a protein that interacts with TGF.beta. proteins. Modulation of the activity of any protein that interacts with LTBP4 is contemplated by the disclosure, and in various embodiments the TGF.beta. protein is selected from the group consisting of a growth and differentiation factor (GDF), activin, inhibin, and a bone morphogenetic protein. TGF.beta. proteins are known in the art and are discussed, for example and without limitation, in Schmierer et al. (Nature Reviews Molecular Cell Biology 8: 970-982 (2007)], incorporated herein by reference. In addition, isoforms of TGF.beta. proteins are contemplated and include, without limitation, TGF.beta. 1, TGF.beta. 2, TGF.beta. 3, GDF 8, and GDF 11.

[0096] Practice of methods of the disclosure wherein a patient is administered one or more agent(s) and optionally additional agent(s) is expected to result in modulation of the activity of a TGF.beta. protein by at least about 1% relative to a patient not so treated. In further embodiments, the activity of a TGF.beta. protein in a patient that is administered one or more agent(s) and/or additional agent(s) is modulated by at least about 1% and up to any one of about 2%, about 5%, about 10% or about 15% TGF.beta. activity relative to a patient not so treated. In still further embodiments, the activity of a TGF.beta. protein in a patient that is administered one or more agent(s) and optionally additional agent(s) is modulated by at least about 10% and up to any one of about 15%, about 20%, about 25% or about 30% TGF.beta. activity relative to a patient not so treated. In further embodiments, the activity of a TGF.beta. protein in a patient that is administered one or more agent(s) and/or additional agent(s) is modulated by at least about 10% and up to any one of about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more TGF.beta. activity relative to a patient not so treated. In specific embodiments, the activity of a TGF.beta. protein in a patient that is administered one or more agent(s) and optionally additional agent(s) is modulated by at least about 1%, about 2%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% TGF.beta. activity or more relative to a patient not so treated. Protein activity may be quantitated by methods generally known to those of skill in the art.

Additional (Second) Agents

[0097] In various embodiments of the disclosure it is contemplated that a second agent is administered with the agent that modulates LTBP4 activity by modulating the proteolysis of LTBP4. Nonlimiting examples of the second agent are a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis. Further, the methods disclosed herein can, in various embodiments, encompass one or more of such agents, or one or more of such agents in composition with any other active agent(s).

Chemotherapeutic Agents

[0098] Chemotherapeutic agents contemplated for use include, without limitation, alkylating agents including: nitrogen mustards, such as mechlor-ethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil; nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU); ethylenimines/methylmelamine such as thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DTIC); antimetabolites including folic acid analogs such as methotrexate and trimetrexate, pyrimidine analogs such as 5-fluorouracil, fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2'-difluorodeoxycytidine, purine analogs such as 6-mercaptopurine, 6-thioguanine, azathioprine, 2'-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, and 2-chlorodeoxyadenosine (cladribine, 2-CdA); natural products including antimitotic drugs such as paclitaxel, vinca alkaloids including vinblastine (VLB), vincristine, and vinorelbine, taxotere, estramustine, and estramustine phosphate; epipodophylotoxins such as etoposide and teniposide; antibiotics such as actimomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin), mitomycin C, and actinomycin; enzymes such as L-asparaginase; biological response modifiers such as interferon-alpha, IL-2, G-CSF and GM-CSF; miscellaneous agents including platinum coordination complexes such as cisplatin and carboplatin, anthracenediones such as mitoxantrone, substituted urea such as hydroxyurea, methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine, adrenocortical suppressants such as mitotane (o,p'-DDD) and aminoglutethimide; hormones and antagonists including adrenocorticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; progestin such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogen such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogen such as tamoxifen; androgens including testosterone propionate and fluoxymesterone/equivalents; antiandrogens such as flutamide, gonadotropin-releasing hormone analogs and leuprolide; and non-steroidal antiandrogens such as flutamide.

Modulators of Fibrosis

[0099] A "modulator of fibrosis" as used herein is synonymous with antifibrotic agent. The term "antifibrotic agent" refers to a chemical compound that has antifibrotic activity (i.e., prevents or reduces fibrosis) in mammals. This takes into account the abnormal formation of fibrous connective tissue, which is typically comprised of collagen. These compounds may have different mechanisms of action, some reducing the formation of collagen or another protein, others enhancing the catabolism or removal of collagen in the affected area of the body. All such compounds having activity in the reduction of the presence of fibrotic tissue are included herein, without regard to the particular mechanism of action by which each such drug functions. Antifibrotic agents useful in the methods and compositions of the disclosure include those described in U.S. Pat. No. 5,720,950, incorporated herein by reference. Additional antifibrotic agents contemplated by the disclosure include, but are not limited to, Type II interferon receptor agonists (e.g., interferon-gamma); pirfenidone and pirfenidone analogs; anti-angiogenic agents, such as VEGF antagonists, VEGF receptor antagonists, bFGF antagonists, bFGF receptor antagonists, TGF.beta. antagonists, TGF.beta. receptor antagonists; anti-inflammatory agents, IL-1 antagonists, such as IL-1Ra, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers and aldosterone antagonists.

Modulators of an Inflammatory Response

[0100] A modulator of an inflammatory response includes the following agents. In one embodiment of the disclosure, the modulator of an inflammatory response is a beta2-adrenergic receptor agonist (e.g., albuterol). The term beta2-adrenergic receptor agonist is used herein to define a class of drugs which act on the .beta.2-adrenergic receptor, thereby causing smooth muscle relaxation resulting in dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle and release of insulin. In one embodiment, the beta2-adrenergic receptor agonist for use according to the disclosure is albuterol, an immunosuppressant drug that is widely used in inhalant form for asthmatics. Albuterol is thought to slow disease progression by suppressing the infiltration of macrophages and other immune cells that contribute to inflammatory tissue loss. Albuterol also appears to have some anabolic effects and promotes the growth of muscle tissue. Albuterol may also suppress protein degradation (possibly via calpain inhibition).

[0101] In DMD, the loss of dystrophin leads to breaks in muscle cell membrane, and destabilizes neuronal nitric oxide synthase (nNOS), a protein that normally generates nitric oxide (NO). It is thought that at least part of the muscle degeneration observed in DMD patients may result from the reduced production of muscle membrane-associated neuronal nitric oxide synthase. This reduction may lead to impaired regulation of the vasoconstrictor response and eventual muscle damage.

[0102] In one embodiment, modulators of an inflammatory response suitable for use in compositions of the disclosure are Nuclear Factor Kappa-B (NF-.kappa.B) inhibitors. NF-.kappa.B is a major transcription factor modulating cellular immune, inflammatory and proliferative responses. NF-.kappa.B functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. The activation of this factor in DMD contributes to diseases pathology. Thus, NF-.kappa.B plays an important role in the progression of muscular dystrophy and the IKK/NF-.kappa.B signaling pathway is a potential therapeutic target for the treatment of a TGF.beta.-related disease. Inhibitors of NF-.kappa.B (for example, IRFI 042, a vitamin E analog) enhance muscle function, decrease serum creatine kinase (CK) level and muscle necrosis and enhance muscle regeneration. Furthermore, specific inhibition of NF-.kappa.B-mediated signaling by IKK has similar benefits.

[0103] In a further embodiment, the modulator of an inflammatory response is a tumor necrosis factor alpha antagonist. TNF-.alpha. is one of the key cytokines that triggers and sustains the inflammation response. In one specific embodiment of the disclosure, the modulator of an inflammatory response is the TNF-.alpha. antagonist infliximab.

[0104] TNF-.alpha. antagonists for use according to the disclosure include, in addition to infliximab (Remicade.TM.), a chimeric monoclonal antibody comprising murine VK and VH domains and human constant Fc domains. The drug blocks the action of TNF-.alpha. by binding to it and preventing it from signaling the receptors for TNF-.alpha. on the surface of cells. Another TNF-.alpha. antagonist for use according to the disclosure is adalimumab (Humira.TM.) Adalimumab is a fully human monoclonal antibody. Another TNF-.alpha. antagonist for use according to the disclosure is etanercept (Enbrel.TM.). Etanercept is a dimeric fusion protein comprising soluble human TNF receptor linked to an Fc portion of an IgG1. It is a large molecule that binds to TNF-.alpha. and thereby blocks its action. Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptors, but as a fusion protein it has a greatly extended half-life in the bloodstream and therefore a more profound and long-lasting inhibitory effect.

[0105] Another TNF-.alpha. antagonist for use according to the disclosure is pentoxifylline (Trental.TM.), chemical name 1-(5-oxohexyl)-3,7-dimethylxanthine. The usual dosage in controlled-release tablet form is one tablet (400 mg) three times a day with meals.

[0106] Dosing: Remicade is administered by intravenous infusion, typically at 2-month intervals. The recommended dose is 3 mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks. Humira is marketed in both preloaded 0.8 ml (40 mg) syringes and also in preloaded pen devices, both injected subcutaneously, typically by the patient at home. Etanercept can be administered at a dose of 25 mg (twice weekly) or 50 mg (once weekly).

[0107] In another embodiment of the disclosure, the modulator of an inflammatory response is cyclosporin. Cyclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids produced by the fungus Tolypocladium inflatum. Cyclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes (especially T-lymphocytes). This complex of cyclosporin and cyclophylin inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. It also inhibits lymphokine production and interleukin release and therefore leads to a reduced function of effector T-cells. It does not affect cytostatic activity. It has also an effect on mitochondria, preventing the mitochondrial PT pore from opening, thus inhibiting cytochrome c release (a potent apoptotic stimulation factor). Cyclosporin may be administered at a dose of 1-10 mg/kg/day.

A Promoter of Muscle Growth

[0108] In some embodiments of the disclosure, a therapeutically effective amount of a promoter of muscle growth is administered to a patient. Promoters of muscle growth contemplated by the disclosure include, but are not limited to, insulin-like growth factor-1 (IGF-1), Akt/protein kinase B, clenbuterol, creatine, decorin (see U.S. Patent Publication Number 20120058955), a steroid (for example and without limitation, a corticosteroid or a glucocorticoid steroid), testosterone and a myostatin antagonist.

Myostatin Antagonist

[0109] Another class of promoters of muscle growth suitable for use in the combinations of the disclosure is myostatin antagonists. Myostatin, also known as growth/differentiation factor 8 (GDF-8) is a transforming growth factor-.beta. (TGF.beta.) superfamily member involved in the regulation of skeletal muscle mass. Most members of the TGF-.beta.-GDF family are widely expressed and are pleiotropic; however, myostatin is primarily expressed in skeletal muscle tissue where it negatively controls skeletal muscle growth. Myostatin is synthesized as an inactive preproprotein which is activated by proteolyic cleavage. The precurser protein is cleaved to produce an approximately 109-amino-acid COOH-terminal protein which, in the form of a homodimer of about 25 kDa, is the mature, active form. The mature dimer appears to circulate in the blood as an inactive latent complex bound to the propeptide. As used herein the term "myostatin antagonist" defines a class of agents that inhibits or blocks at least one activity of myostatin, or alternatively, blocks or reduces the expression of myostatin or its receptor (for example, by interference with the binding of myostatin to its receptor and/or blocking signal transduction resulting from the binding of myostatin to its receptor). Such agents therefore include agents which bind to myostatin itself or to its receptor.

[0110] Myostatin antagonists for use according to the disclosure include antibodies to GDF-8; antibodies to GDF-8 receptors; soluble GDF-8 receptors and fragments thereof (e.g., the ActRIIB fusion polypeptides as described in U.S. Patent Publication Number 2004/0223966, which is incorporated herein by reference in its entirety, including soluble ActRIIB receptors in which ActRIIB is joined to the Fc portion of an immunoglobulin); GDF-8 propeptide and modified forms thereof (e.g., as described in WO 2002/068650 or U.S. Pat. No. 7,202,210, including forms in which GDF-8 propeptide is joined to the Fc portion of an immunoglobulin and/or form in which GDF-8 is mutated at an aspartate (asp) residue, e.g., asp-99 in murine GDF-8 propeptide and asp-100 in human GDF-8 propeptide); a small molecule inhibitor of GDF-8; follistatin (e.g., as described in U.S. Pat. No. 6,004,937, incorporated herein by reference) or follistatin-domain-containing proteins (e.g., GASP-1 or other proteins as described in U.S. Pat. Nos. 7,192,717 and 7,572,763, each incorporated herein by reference); and modulators of metalloprotease activity that affect GDF-8 activation, as described in U.S. Patent Publication Number 2004/0138118, incorporated herein by reference.

[0111] Additional myostatin antagonists include myostatin antibodies which bind to and inhibit or neutralize myostatin (including the myostatin proprotein and/or mature protein, in monomeric or dimeric form). Myostatin antibodies are mammalian or non-mammalian derived antibodies, for example an IgNAR antibody derived from sharks, or humanized antibodies, or comprise a functional fragment derived from antibodies. Such antibodies are described, for example, in WO 2005/094446 and WO 2006/116269, the content of which is incorporated herein by reference. Myostatin antibodies also include those antibodies that bind to the myostatin proprotein and prevent cleavage into the mature active form. Additional antibody antagonists include the antibodies described in U.S. Pat. Nos. 6,096,506 and 6,468,535 (each of which is incorporated herein by reference). In some embodiments, the GDF-8 inhibitor is a monoclonal antibody or a fragment thereof that blocks GDF-8 binding to its receptor. Further embodiments include murine monoclonal antibody JA-16 (as described in U.S. Pat. No. 7,320,789 (ATCC Deposit No. PTA-4236); humanized derivatives thereof and fully human monoclonal anti-GDF-8 antibodies (e.g., Myo29, Myo28 and Myo22, ATCC Deposit Nos. PTA-4741, PTA-4740, and PTA-4739, respectively, or derivatives thereof) as described in U.S. Pat. No. 7,261,893 and incorporated herein by reference.

[0112] In still further embodiments, myostatin antagonists include soluble receptors which bind to myostatin and inhibit at least one activity thereof. The term "soluble receptor" herein includes truncated versions or fragments of the myostatin receptor that specifically bind myostatin thereby blocking or inhibiting myostatin signal transduction. Truncated versions of the myostatin receptor, for example, include the naturally occurring soluble domains, as well as variations produced by proteolysis of the N- or C-termini. The soluble domain includes all or part of the extracellular domain of the receptor, either alone or attached to additional peptides or other moieties. Because myostatin binds activin receptors (including the activin type IEB receptor (ActRHB) and activin type HA receptor (ActRHA)), activin receptors can form the basis of soluble receptor antagonists. Soluble receptor fusion proteins can also be used, including soluble receptor Fc (see U.S. Patent Publication Number 2004/0223966 and WO 2006/012627, both of which are incorporated herein by reference in their entireties).

[0113] Other myostatin antagonists based on the myostatin receptors are ALK-5 and/or ALK-7 inhibitors (see for example WO 2006/025988 and WO 2005/084699, each incorporated herein by reference). As a TGF-.beta. cytokine, myostatin signals through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided in two classes, the type I or activin-like kinase (ALK) receptors and type II receptors. The ALK receptors are distinguished from the Type II receptors in that the ALK receptors (a) lack the serine/threonine-rich intracellular tail, (b) possess serine/threonine kinase domains that are highly homologous among Type I receptors, and (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is believed to be critical for activation by the Type II receptor. Several studies have shown that TGF-.beta. signaling requires both the ALK (Type I) and Type II receptors. Specifically, the Type II receptor phosphorylates the GS domain of the Type 1 receptor for TGF.beta. ALK5, in the presence of TGF.beta.. The ALK5, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. Generally, it is believed that in many species, the Type II receptors regulate cell proliferation and the Type I receptors regulate matrix production. Various ALK5 receptor inhibitors have been described (see, for example, U.S. Pat. Nos. 6,465,493, 6,906,089, U.S. Patent Publication Numbers 2003/0166633, 2004/0063745 and 2004/0039198, the disclosures of which are incorporated herein by reference). Thus, the myostatin antagonists for use according to the disclosure may comprise the myostatin binding domain of an ALK5 and/or ALK7 receptor.

[0114] Other myostatin antagonists include soluble ligand antagonists that compete with myostatin for binding to myostatin receptors. The term "soluble ligand antagonist" herein refers to soluble peptides, polypeptides or peptidomimetics capable of non-productively binding the myostatin receptor(s) (e.g., the activin type HB receptor (ActRHA)) and thereby competitively blocking myostatin-receptor signal transduction. Soluble ligand antagonists include variants of myostatin, also referred to as "myostatin analogs" that have homology to, but not the activity of, myostatin. Such analogs include truncates (such as N- or C-terminal truncations, substitutions, deletions, and other alterations in the amino acid sequence, such as variants having non-amino acid substitutions).

[0115] Additional myostatin antagonists contemplated by the disclosure include inhibitory nucleic acids as described herein. These antagonists include antisense or sense polynucleotides comprising a single-stranded polynucleotide sequence (either RNA or DNA) capable of binding to target mRNA (sense) or DNA (antisense) sequences. Thus, RNA interference (RNAi) produced by the introduction of specific small interfering RNA (siRNA), may also be used to inhibit or eliminate the activity of myostatin.

[0116] In specific embodiments, myostatin antagonists include, but are not limited to, follistatin, the myostatin prodomain, growth and differentiation factor 11 (GDF-11) prodomain, prodomain fusion proteins, antagonistic antibodies or antibody fragments that bind to myostatin, antagonistic antibodies or antibody fragments that bind to the activin type IEB receptor, soluble activin type IHB receptor, soluble activin type IEB receptor fusion proteins, soluble myostatin analogs (soluble ligands), polynucleotides, small molecules, peptidomimetics, and myostatin binding agents. Other antagonists include the peptide immunogens described in U.S. Pat. No. 6,369,201 and WO 2001/05820 (each of which is incorporated herein by reference) and myostatin multimers and immunoconjugates capable of eliciting an immune response and thereby blocking myostatin activity. Other antagonists include the protein inhibitors of myostatin described in WO 2002/085306 (incorporated herein by reference), which include the truncated Activin type II receptor, the myostatin pro-domain, and follistatin. Other myostatin inhibitors include those released into culture from cells overexpressing myostatin (see WO 2000/43781), dominant negative myostatin proteins (see WO 2001/53350) including the protein encoded by the Piedmontese allele, and mature myostatin peptides having a C-terminal truncation at a position either at or between amino acid positions 335 to 375. The small peptides described in U.S. Patent Publication Number 2004/0181033 (incorporated herein by reference) that comprise the amino acid sequence WMCPP, are also suitable for use in the compositions of the disclosure.

Vectors

[0117] An appropriate expression vector may be used to deliver exogenous nucleic acid to a recipient muscle cell in the methods of the disclosure. In order to achieve effective gene therapy, the expression vector must be designed for efficient cell uptake and gene product expression. Use of adenovirus or adeno-associated virus (AAV) based vectors for gene delivery have been described [Berkner, Current Topics in Microbiol. and Imunol. 158: 39-66 (1992); Stratford-Perricaudet et al., Hum. Gene Ther. 1: 241-256 (1990); Rosenfeld et al., Cell 8: 143-144 (1992); Stratford-Perricaudet et al., J. Clin. Invest. 90: 626-630 (1992)]. In one specific embodiment, the adeno-associated virus vector is AAV9. Specific methods for gene therapy useful in the context of the present disclosure depend largely upon the expression system employed; however, most methods involve insertion of coding sequence at an appropriate position within the expression vector, and subsequent delivery of the expression vector to the target muscle tissue for expression.

[0118] Additional delivery systems useful in the practice of the methods of the disclosure are discussed in U.S. Patent Publication Numbers 2012/0046345 and 2012/0039806, each of which is incorporated herein by reference in its entirety.

Therapeutic Endpoints

[0119] In various aspects of the disclosure, use of the agent(s) and optional additional agent(s) as described herein provide one or more benefits related to specific therapeutic endpoints relative to a patient not receiving the agent(s) and/or additional agent(s).

[0120] In embodiments wherein the TGF.beta.-related disease is a muscle-related disease (e.g., a muscular dystrophy or cardiomyopathy), therapeutic endpoints include, but are not limited to, length of time until a patient is non-ambulatory, ambulatory capacity as measured by, for example and without limitation, six-minute-walk distance which has been shown to correlate with human LTBP4 SNPs [see, for example, Hersh et al., Am J Respir Crit Care Med. 173(9): 977-84 (2006)], relative health of heart as determined by, e.g., echocardiography, magnetic resonance imaging (MRI), muscle mechanics, pulmonary function and/or amount of tissue fibrosis.

[0121] With respect to the length of time until a patient is non-ambulatory, it is contemplated that, in some embodiments, a patient that is administered one or more agent(s) and, optionally, additional agent(s) remains ambulatory at least 1 day and up to any of about 5, about 10, about 30, about 60 or about 90 days longer than a patient not so treated. In further embodiments, a patient that is administered one or more agent(s) and optional additional agent(s) remains ambulatory at least about 1 month and up to any of about 2, about 4, about 6, about 8, about 10 or about 12 months longer than a patient not so treated. Still further embodiments of the disclosure contemplate that a patient that is administered one or more agent(s) and, optionally, additional agent(s) remains ambulatory at least about 1 year and up to any of about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10 or more years longer than a patient not so treated.

[0122] In embodiments wherein the TGF.beta.-related disease is a cancer, therapeutic endpoints include but are not limited to a reduction in tumor volume (i.e., the size of the tumor measured by the amount of space taken up by it expressed in traditional units of volume (e.g., cubic centimeters) or as a percentage of the tissue or organ within which it is found (e.g., the tumor volume of prostate cancer is the percentage of the prostate taken up by the tumor)) and/or a reduction in metastasis. With respect to the reduction in tumor volume and/or a reduction in metastasis, it is contemplated that in some embodiments the tumor volume or amount of metastasis is reduced in a patient that is administered one or more agent(s) and, optionally, additional agent(s) by about 1% relative to a patient not so treated. In further embodiments, the tumor volume or amount of metastasis is reduced in a patient that is administered one or more agent(s) and, optionally, additional agent(s) by at least about 1% and up to any of about 2%, about 5%, about 10% or about 15% relative to a patient not so treated. In still further embodiments, the tumor volume or amount of metastasis is reduced in a patient that is administered one or more agent(s) and, optionally, additional agent(s) by at least about 10% and up to about 15%, about 20%, about 25% or about 30% relative to a patient not so treated. In further embodiments, the tumor volume or amount of metastasis is reduced in a patient that is administered one or more agent(s) and, optionally, additional agent(s) by at least about 10% and up to any of about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more relative to a patient not so treated. In specific embodiments, the tumor volume or amount of metastasis is reduced in a patient that is administered one or more agent(s) and, optionally, additional agent(s) by at least about 1%, about 2%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more relative to a patient not so treated. Methods of measuring tumor volume as well as amount of metastasis are known in the art.

[0123] In embodiments wherein the TGF.beta.-related disease is a viral disease, therapeutic endopoints relate to the viral load in the patient. Methods of determining viral load are well known in the art and can be quantitated using methods such as polymerase chain reaction (PCR), reverse-transcriptase PCR (RT-PCR), probe-specific amplification or by the branched DNA (bDNA) method. In various embodiments, the viral load of a patient being administered one or more agent(s) and, optionally, additional agent(s) of the disclosure is reduced by at least about 1% and up to any of about 5%, about 10%, about 20%, about 30%, about 40% or about 50% relative to a patient not so treated. In further embodiments, the viral load of a patient being administered one or more agent(s) and, optionally, additional agent(s) of the disclosure is reduced by at least about 10% and up to any of about 20%, about 50%, about 70%, about 80%, about 90%, about 99% or more relative to a patient not so treated. In specific embodiments, the viral load of a patient being administered one or more agent(s) and/or additional agent(s) of the disclosure is reduced by at least about 1%, about 2%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more relative to a patient not so treated.

[0124] In general, a therapeutic endpoint achieved by practice of the methods of the disclosure is a reduction in the amount of fibrosis in a patient being administered one or more agent(s) and, optionally, additional agent(s) of the disclosure. Relative amounts of fibrosis in a patient can be quantitated by tissue biopsy and subsequent histology, e.g., by quantifying Evans blue dye uptake as a measure of myofiber or cellular damage [Heydemann et al., Neuromuscular Disorders 15(9-10): 601-9 (2005)], and/or quantitation of hydroxyproline content as described previously [Swaggart et al., Physiol Genomics 43: 24-31 (2011)]. In various embodiments, the amount of fibrosis in a patient being administered one or more agent(s) and, optionally, additional agent(s) of the disclosure is reduced by at least about 1% and up to any of about 5%, about 10%, about 20%, about 30%, about 40% or about 50% relative to a patient not so treated. In further embodiments, the amount of fibrosis in a patient being administered one or more agent(s) and, optionally, additional agent(s) of the disclosure is reduced by at least about 10% and up to about 20%, about 50%, about 70%, about 80%, about 90%, about 99% or more relative to a patient not so treated. In specific embodiments, the amount of fibrosis in a patient being administered one or more agent(s) and/or additional agent(s) of the disclosure is reduced by at least about 1%, about 2%, about 5%, about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more relative to a patient not so treated.

[0125] The amount of fibrosis in a patient can be routinely determined by one of ordinary skill in the art. For example, and without limitation, the amount of fibrosis can be determined by taking a muscle biopsy from a patient, sectioning the muscle onto slides and assessing the amount of fibrosis as revealed by staining techniques known in the art (e.g., Hematoxylin and Eosin (H&E) staining and/or Masson's trichrome staining). Alternatively, or in addition, the amount of fibrosis can be determined in vivo by using magnetic resonance imaging (MRI).

Dosing/Administration/Kits

[0126] A particular administration regimen for a particular subject will depend, in part, upon the agent and optional additional agent used, the amount of the agent and optional additional agent administered, the route of administration, the particular ailment being treated, and the cause and extent of any side effects. The amount of agent and optional additional agent administered to a subject (e.g., a mammal, such as a human) is sufficient to effect the desired response. Dosage typically depends upon a variety of factors, including the particular agent and/or additional agent employed, the age and body weight of the subject, as well as the existence and severity of any disease or disorder in the subject. The size of the dose also will be determined by the route, timing, and frequency of administration. Accordingly, the clinician may titer the dosage and modify the route of administration to obtain optimal therapeutic effect, and conventional range-finding techniques are known to those of ordinary skill in the art. Purely by way of illustration, in some embodiments, the method comprises administering, e.g., from about 0.1 .mu.g/kg up to about 100 mg/kg or more, depending on the factors mentioned above. In other embodiments, the dosage may range from 1 .mu.g/kg up to about 75 mg/kg; or 5 .mu.g/kg up to about 50 mg/kg; or 10 .mu.g/kg up to about 20 mg/kg. In certain embodiments, the dose comprises about 0.5 mg/kg to about 20 mg/kg (e.g., about 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.3 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, or 10 mg/kg) of agent and optional additional agent. In embodiments in which an agent and additional agent are administered, the above dosages are contemplated to represent the amount of each agent administered, or in further embodiments the dosage represents the total dosage administered. Given the chronic nature of many TGF.beta.-related disorders, it is envisioned that a subject will receive the agent and/or additional agent over a treatment course lasting weeks, months, or years, and may require one or more doses daily or weekly. Dosages are also contemplated for once daily, twice daily (BID) or three times daily (TID) dosing. A unit dose may be formulated in either capsule or tablet form. In other embodiments, the agent and optional additional agent is administered to treat an acute condition (e.g., acute muscle injury or acute myocardial injury) for a relatively short treatment period, e.g., one to 14 days.

[0127] Suitable methods of administering a physiologically-acceptable composition, such as a pharmaceutical composition comprising an agent and optional additional agent described herein, are well known in the art. Although more than one route can be used to administer an agent and/or additional agent, a particular route can provide a more immediate and more effective avenue than another route. Depending on the circumstances, a pharmaceutical composition is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and/or introduced into circulation. In some embodiments, a composition comprising an agent and/or additional agent is administered intravenously, intraarterially, or intraperitoneally to introduce an agent and optional additional agent into circulation. Non-intravenous administration also is appropriate, particularly with respect to low molecular weight therapeutics. In certain circumstances, it is desirable to deliver a pharmaceutical composition comprising the agent and/or additional agent orally, topically, sublingually, vaginally, rectally; through injection by intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intranasal, urethral, or enteral means; by sustained release systems; or by implantation devices. If desired, the agent and/or additional agent is administered regionally via intraarterial or intravenous administration to a region of interest, e.g., via the femoral artery for delivery to the leg. In one embodiment, the composition is administered via implantation of a membrane, sponge, or another appropriate material within or upon which the desired agent and optional additional agent has been absorbed or encapsulated. Where an implantation device is used, the device in one aspect is implanted into any suitable tissue, and delivery of the desired agent and/or additional agent is, in various embodiments, effected via diffusion, time-release bolus, or continuous administration. In other embodiments, the agent and optional additional agent is administered directly to exposed tissue during surgical procedures or treatment of injury, or is administered via transfusion of blood products. Therapeutic delivery approaches are well known to the skilled artisan, some of which are further described, for example, in U.S. Pat. No. 5,399,363.

[0128] In some embodiments facilitating administration, the agent and optional additional agent in one embodiment is formulated into a physiologically-acceptable composition comprising a carrier (i.e., vehicle, adjuvant, buffer, or diluent). The particular carrier employed is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the agent and/or additional agent, by the route of administration, and by the requirement of compatibility with the recipient organism. Physiologically acceptable carriers are well known in the art. Illustrative pharmaceutical forms suitable for injectable use include, without limitation, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Pat. No. 5,466,468). Injectable formulations are further described in, e.g., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia. Pa., Banker and Chalmers. eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986), incorporated herein by reference).

[0129] A pharmaceutical composition comprising an agent and optional additional agent as provided herein is optionally placed within containers/kits, along with packaging material that provides instructions regarding the use of such pharmaceutical compositions. Generally, such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents that may be necessary to reconstitute the pharmaceutical composition.

[0130] The disclosure thus includes administering to a subject one or more agent(s), in combination with one or more additional agent(s), each being administered according to a regimen suitable for that medicament. Administration strategies include concurrent administration (i.e., substantially simultaneous administration) and non-concurrent administration (i.e., administration at different times, in any order, whether overlapping or not) of the agent and one or more additional agents(s). It will be appreciated that different components are optionally administered in the same or in separate compositions, and by the same or different routes of administration.

[0131] All publications, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In addition, the entire document is intended to be related as a unified disclosure, and it should be understood that all combinations of features described herein are contemplated, even if the combination of features are not found together in the same sentence, or paragraph, or section of this document. For example, where protein therapy is described, embodiments involving polynucleotide therapy (using polynucleotides/vectors that encode the protein) are specifically contemplated, and the reverse also is true. With respect to elements described as one or more members of a set, it should be understood that all combinations within the set are contemplated.

EXAMPLES

Example 1

Structure-Function Relationship Between the Proline-Rich Region of LTBP4 and Proteolytic Susceptibility

[0132] The data provided in this Example show that the proline-rich region of LTBP4 contributes to its proteolytic susceptibility.

[0133] LTBP4 binds to TGF.beta. in the extracellular matrix (ECM), where it serves as a readily available TGF.beta. storage site. A 36-nucleotide deletion was identified in the proline-rich domain of murine LTBP4 that associates with enhanced pathogenic features of muscular dystrophy in mice. This region in murine LTBP4 is associated with variable susceptibility to proteolysis. Sequence comparison analysis between LTBP4 from mouse and humans reveals an even larger deletion in the proline-rich region of human LTBP4. Thus, consistent with the murine deletion being associated with pathogenic features and variable proteolysis [see Heydemann et al., J Clin Invest. 119(12): 3703-12 (2009)], it was contemplated that the larger deletion of the proline-rich region of human LTBP4 was associated with enhanced susceptibility to proteolytic cleavage.

[0134] To investigate this possibility, a portion of the human LTBP4 coding region was ligated into an expression vector to express the proline-rich region. The TP fragment (amino acids 483-565 of the human LTBP4 protein (SEQ ID NO: 1)) was expressed and migrated as a 3.5 KDa protein although its predicted molecular mass is 8.9 KDa. A second fragment, TP2E fragment (amino acids 357-586 of the human LTBP4 protein (SEQ ID NO: 1)) was also expressed. Its predicted molecular mass is 24.5 KDa, yet it electrophoretically migrated as a 31 KDa protein. TP2E included the two EGF-like domains that flank the proline-rich region of LTBP4 along with the amino terminal 8-cysteine rich region immediately amino-terminal of the proline-rich region. Murine TP2E and TP each contained an additional 44 amino acids compared to the human sequences, reflecting the larger proline-rich region. The murine TP2E electrophoretically migrates as a 35 KDa protein while its calculated molecular mass is 30.58 KDa.

Susceptibility to Proteolysis in Vitro

[0135] Human and mouse TP2E fragments were expressed in vitro using a transcription-translation coupled assay (Promega TnT.RTM. Quick Coupled in vitro Transcription/Translation System) and the expressed fragments were labeled using .sup.35S-Cysteine. Dose-response and time course experiments were performed with elastase and plasmin, which are both serine proteases that cleave LTBP4, to determine the differential digestion of the human and mouse TP2E fragments. Data from these experiments showed that the human TP2E fragment is more readily cleaved than the mouse LTBP4 sequence (FIG. 3).

Effects of Smaller Fragments of LTBP4 on TGF.beta. Signaling

[0136] An antibody to the proline-rich region of human LTBP4 was generated to inhibit LTBP4 cleavage. This antibody was tested and confirmed to recognize and bind to the full-length human LTBP4 by immunoblot. Conditions were then optimized for the digestion of full-length human LTBP4 by plasmin, and inhibition of proteolysis using the antibody was tested. The data in FIG. 4 show that the anti-LTBP4 antibody specifically inhibited the protein digestion compared to a nonrelated antibody raised in the same species (FIG. 4).

Example 2

Effect of Human LTBP4 Expression on Muscle and Cardiac Phenotypes

[0137] LTBP4 plays a critical role in TGF.beta. secretion and activation in cardiac muscle, skeletal muscle and lung. Human LTBP4 has a larger deletion in the proline-rich region compared to a mutant murine LTBP4, with wild-type murine LTBP4 used as a reference. Thus, it is contemplated that human LTBP4 is associated with increased pathogenic TGF.beta. signaling and, therefore, will be associated with more severe disease in mice with muscular dystrophy.

Transgenic Mice Expressing Human LTBP4

[0138] A mouse harboring the human LTBP4 gene was generated according to standard protocols [see, e.g., Heintz, Nat Rev Neurosci. 2(12):861-70 (2001)]. A bacterial artificial chromosome (BAC) that included the complete human LTBP4 gene; the BAC transgenic-positive (Tg+) mice are referred to as hLTBP4 Tg+. To generate the hLTBP4 Tg+mice, a single, unmodified BAC clone (clone number CDT-2166J9) was used to inject a fertilized oocyte using conventional methodology [see, e.g., Heintz, Nat Rev Neurosci. 2(12):861-70 (2001)]. The human sequence of this BAC (Genbank accession number AC010412.9; SEQ ID NO: 7) contains 155085 bp from chromosome 19. The LTBP4 gene spans from 19891 to 57891 bp of this clone. Eleven founder lines were evaluated by PCR and found to contain the full-length human LTBP4, including promoter regions. Six lines were chosen for breeding to ensure that these mice were passing the BAC in their germline. By RT-PCR, it was determined that the human LTBP4 mRNA was expressed in cardiac and skeletal muscle of the transgenic mice. At present, there is no antibody that distinguishes human LTBP4 from mouse LTBP4; human and mouse LTBP4 are 98% similar. Overall, LTBP4 expression may be slightly elevated in hLTBP4 Tg+mice compared to littermate controls. hLTBP4 Tg+ mice are outwardly normal and breed normally. Histological examination showed grossly normal histology in brain, kidney, lung, heart and muscle. Interestingly, hLTBP4 Tg+ skeletal muscle fibers were significantly larger than littermate control transgene negative mice. It is contemplated that even modest overexpression of LTBP4 may be sufficient to bind other TGF.beta. superfamily members such as myostatin, and sequestration of myostatin would inhibit myostatin activity and would be expected to result in larger muscle fibers.

[0139] The hLTBP4 Tg+ animal will be bred to the mouse mdx model of Duchenne Muscular Dystrophy and the phenotype and TGF.beta. signaling capacity will be assessed. Ten mice of each genotype (hLTBP4 Tg+/mdx, mdx, hLTBP4+ and WT) will be generated. Basic neuromuscular function will be evaluated using SHIRPA protocols. SHIRPA is a combination of neurological tests that assess neuromuscular function [Rafael et al., Mamm Genome. 11(9): 725-8 (2000)]. For example and without limitation, grip strength, running capacity, wire maneuver and rotorod are basic tests that will be used to assess muscle function. In addition, cardiac function will be assessed using echocardiography, and histology will be performed to evaluate fibrosis and membrane permeability using Evans blue dye uptake. All analyses will be conducted on male mice at 8 weeks of age. A cohort of mice will also be aged to examine the effect on mice at a later time point(s). Fibroblasts will also be isolated from these mice to determine their level of SMAD signaling using methods as previously described [Heydemann et al., J Clin Invest. 119(12): 3703-12 (2009)]. It is expected that insertion of the human LTBP4 will result in increased SMAD signaling and enhancement of the mdx phenotype.

Example 3

LTBP4 Peptides and Antibody Generation

[0140] Antibodies were generated using multiple different peptides including the mouse and human LTBP4 sequences (see Table 1, below). Each of the peptides in Table 1 cross reacts to the human protein as determined by immunoblotting. A longer LTBP4 peptide, FLPTHRLEPRPEPRPDPRPGPELPLPSIPAWTGPEIPESGPSS (SEQ ID NO: 6), is also contemplated for use according to the disclosure. Humanized monoclonal antibodies directed against LTBP4 will also be generated.

TABLE-US-00001 TABLE 1 Western Antibody Antigen Blot Results on Name Species Peptide Used Source Activity Proteolysis mLTBP4d36-829 chicken EPRPRPEPRPQPESQPWP Mouse-D2 +++ NA (SEQ ID NO: 2) mLTBP4d36-830 chicken EPRPRPEPRPQPESQPWP Mouse-D2 ++ NA (SEQ ID NO: 2) hLTBP4pr-831 chicken EPRPEPRPDPRPGPELP Human ++++ positive (SEQ ID NO: 3) hLTBP4pr-832 chicken EPRPEPRPDPRPGPELP Human ++ NA (SEQ ID NO: 3) mLTBP4ins-24226 rabbit ESQPRPESRPRPESQPWP Mouse-129 ++ NA (SEQ ID NO: 4) mLTBP4ins-24226 rabbit ESQPRPESRPRPESQPWP Mouse-129 ++ NA (SEQ ID NO: 4) hLTBP4(511-530) rabbit EPRPEPRPDPRPGPELPLP Human NA NA 28200 (SEQ ID NO: 5) hLTBP4(511-530) rabbit EPRPEPRPDPRPGPELPLP Human NA NA 28199 (SEQ ID NO: 5) LTBP4 peptides used for antibody generation. "Species" indicates antibody source.

[0141] Table 1 shows that each antibody recognized a protein the size of human LTBP4, as determined by immunoblot. The data in the table also indicates that the antibody raised against the human sequence (SEQ ID NO: 3) protects LTBP4 against proteolysis in vitro (FIG. 6, described below) and, given the cross reactivity, the other anti-hLTBP4 antibodies are also expected to protect hLTBP4 from proteolysis. Enzyme-linked immunosorbent assays (ELISA) will also be performed to compare the relative affinity of antibodies to each peptide using serum and purified antibodies.

Proteolysis of LTBP4 can be Inhibited with LTBP4 Antibodies

[0142] It was contemplated that the insertion/deletion polymorphism in murine Ltbp4 discussed hereinabove indicated that the proline-rich region is important since the presence or absence of 12 additional amino acids in this region explains its ability to reduce membrane leak and suppress fibrosis, two activities that were attributed to LTBP4's ability to sequester TGF.beta.. This position is consistent with the differential sensitivity to proteolysis of the various forms of LTBP4 and the associated TGF.beta. activity in the form of nuclear pSMAD [Heydemann et al., J Clin Invest. 119: 3703-12 (2009)].

[0143] To demonstrate that the proline-rich region of human LTBP4 was susceptible to proteolysis, protein domains were expressed using in vitro transcription and translation according to methods as previously described [Heydemann et al., J Clin Invest. 119(12): 3703-12 (2009)]. By design, only the carboxy-terminus of these expressed proteins was labeled. The expressed fragments were exposed to plasmin. Murine LTBP4 with the 12-amino-acid insertion was largely resistant to proteolysis while the murine LTBP4 deleted for the 12 amino acids was readily degraded (FIG. 5, middle and right lanes). The human LTBP4 was most readily degraded (FIG. 5, left lanes). Similar results were obtained with elastase. It is contemplated that this region (i.e., the region included in the TP and TP2E sequences) is a general serine protease target. Antibodies were generated that were directed at the proline-rich region and it was found that these antibodies inhibited LTBP4 cleavage in vitro (FIG. 6). A nonspecific antibody generated from the same species showed no blocking effect. Additional anti-LTBP4 antibodies have been generated, and Fab fragments will be purified and tested because these fragments are expected to be more useful for in vivo delivery.

[0144] Full-length LTBP4 protein, produced from cultured cells, is also susceptible to plasmin proteolysis (FIG. 6). With muscle injury, such as the injury that occurs in DMD, release of proteases into the extracellular matrix is expected to result in LTBP4 cleavage. The sources of these proteases in vivo may be inflammatory cells, fibroblasts or the myofibers. Increased LTBP4 cleavage was shown to correlate with increased fibrosis, increased muscle membrane leak, increased muscle weakness and increased TGF.beta. signaling [Heydemann et al., J Clin Invest. 119(12): 3703-12 (2009)]. Reduction of TGF.beta. signaling was shown to improve outcome in muscular dystrophy [Cohn et al., Nat Med. 13(2): 204-10 (2007); Goldstein et al., Hum Mol Genet. 20(5): 894-904 (2011)].

[0145] This example demonstrates that proteolysis of the proline-rich region of LTBP4 can be inhibited by antibodies provided herein.

Example 4

Transgenic Mice Harboring Human Ltbp4

[0146] A human bacterial artificial chromosome (BAC) carrying the full length human LTBP4 gene was isolated and characterized. This BAC was injected into mice and several lines of transgenic mice were characterized. Human LTBP4 (hLTBP4-BAC) transgenic mice were bred to mdx mice. The human LTBP4 BAC in the normal background resulted in larger myofiber diameter, a sign of hypertrophy. When the human LTBP4 BAC was in the mdx background, it resulted in enhanced fibrosis in skeletal and cardiac muscle as well as reduced grip strength, relative to control mice that did not carry the transgene (FIG. 7). This supports the observation that the human LTBP4 sequence, with its larger deletion in the proline-rich region, enhances the muscular dystrophy phenotype. These mice will be further used to test whether antibodies directed against human LTBP4 can reduce muscular dystrophy fibrosis and muscle membrane leakage.

Example 5

In Vivo Studies

[0147] Short-term studies are conducted in dystrophic mice (i.e., mdx and limb girdle muscular dystrophy (LGMD)) to determine safety and efficacy of inhibiting LTBP4 cleavage in vivo. Animals are treated from 3 weeks to 8 weeks of age with antibody injections, three times weekly, delivered via intraperitoneal injection. Dose responsiveness is determined. Echocardiography, plethysmography, muscle harvest and ex vivo muscle mechanics are conducted on treated animals and controls. Target tissues are studied, including heart, diaphragm, quadriceps, gluteus/hamstrings, gastrocnemius/soleus, triceps and abdominal muscles, according to previously identified protocols [Heydemann et al., Neuromuscul Disord. 15: 601-9 (2005); Heydemann, et al., J Clin Invest. 119: 3703-12 (2009); Swaggart et al., Physiol Genomics. 43: 24-31 (2011)]. TGF.beta. signaling is also determined.

[0148] Long-term studies are conducted in dystrophic mice to determine the safety and efficacy of the treatment. Once dosing has been determined, cohorts of mice are treated from 3 weeks until 1 year of age. A similar analysis of efficacy are undertaken, as discussed above (i.e., echocardiography, plethysmography, muscle harvest and ex vivo muscle mechanics). Analysis of other organs, including lung, colon, kidney, brain, and other tissues, is included. Mice that are null for LTBP4 develop cardiomyopathy, pulmonary fibrosis and colon cancer. Because LTBP4 is not ablated in these studies, these cardiomyopathy, pulmonary fibrosis and colon cancer defects are not expected, consistent with the results of the genetic studies described above. Nonetheless, off-target tissues are also analyzed.

[0149] The studies described above are expected to show that inhibition of LTBP4 cleavage in vivo results in decreased TGF.beta. signaling, which is further expected to lead to a decrease in membrane permeability as well as a decrease in fibrosis in the muscles of dystrophic mice. These results will be evidenced by an improvement or lack of decline in therapeutic endpoints as described herein, thereby establishing that blockage of LTBP4 proteolysis is a robust therapeutic in the treatment of TGF.beta. superfamily protein-related diseases.

Example 6

LTBP4 Interacts with Myostatin in Vitro

[0150] The ability of LTBP4 to directly interact with myostatin, a TGF-.beta. superfamily member, was also investigated. The methods used to investigate the interaction were as follows. Full length LTBP4 was cloned into an expression vector (pcDNA3.1, Life Technologies (Invitrogen), Grand Island, N.Y.) and the Xpress epitope tag (Life Technologies (Invitrogen), Grand Island, N.Y.) was added to its 5' end/amino terminus. Full-length myostatin, encoding the propeptide and mature regions, was tagged at its 3' end/carboxy terminus with the myc epitope tag. Both plasmids were introduced into HEK293 (Human Embryonic Kidney 293) cells. The cells were lysed and the proteins were blotted or immunoprecipitated with either antibody 28200 or, in a separate experiment, antibody 28199 (see Table 1). Both of these rabbit polyclonal antibodies are directed at the LTBP4 proline-rich region. The immunoprecipitated material was then blotted with the anti-myc antibody, showing that myostatin associates with LTBP4 (FIG. 8).

[0151] This Example shows that LTBP4 is able to directly interact with myostatin. The results indicate that, by inhibiting the proteolysis of LTBP4 according to the present disclosure, one can sequester myostatin and prevent its activation and resultant downstream signaling. Because myostatin is a known negative regulator of muscle growth, the inhibition of myostatin signaling is expected to result in increased muscle growth and increased muscle strength.

Example 7

Expression of Human LTBP4 in Mice Leads to Enhanced Damage after Cardiotoxin Injury

[0152] Mice were generated to express the human LTBP4 gene on a bacterial artificial chromosome, and these transgenic mice were referred to as hLTBP4 Tg+ mice. The human LTBP4 protein is more readily proteolyzed because of its shorter proline-rich region. This increased proteolysis leads to enhanced damage in muscle due to increased TGF.beta. release. Cardiotoxin was injected into the tibialis anterior muscle of normal (WT w/CTX) and hLTBP4 transgenic mice (hLTBP4 Tg+ w/CTX). Transgenic mice displayed enhanced injury after cardiotoxin injury seen as greater inflammatory mononuclear cell infiltrate and fibrosis and fat deposition into the injured muscle (FIG. 9A), similar to what is seen in muscular dystrophy.

[0153] Normal (WT) and hLTBP4 muscle were injected with cardiotoxin to induce injury. Immunoblotting with an anti-LTBP4 antibody showed increased levels of LTBP4 protein induced by injury in both normal and in hLTBP4 transgenic muscle (FIG. 9B). hLTBP4 muscle was also found to be associated with increased TGF.beta. signaling seen as nuclear localized phosphorylated SMAD.

[0154] The results showed that expression of human LTBP4 protein in muscle leads to enhanced muscle damage following cardiotoxin injury.

Example 8

Anti-LTBP4 Antibodies Mitigate Muscle Injury in Vivo

[0155] To test whether anti-LTBP4 antibody mitigated skeletal muscle injury in muscular dystrophy, experiments were carried out using hLTBP4/mdx mice. Cardiotoxin, which is known to cause necrosis of skeletal muscle cells, was injected into the tibialis anterior muscle to induce enhanced injury. This injury model resolves within 2 weeks because a low-volume injection of 10 .mu.l is used. hLTBP4/mdx mice (8 weeks of age) were pretreated on day 0 with either (i) PBS or (ii) antibody to LTBP4-831 antibody at 5 mg/Kg intraperitoneally. On day 1, cardiotoxin was injected into the tibialis anterior muscle. LTBP4-831 antibody was injected on days 1, 3, and 5, each time delivering a 5 mg/Kg dose intraperitoneally. Mice were sacrificed on day 7 and tibialis anterior muscle was harvested for study. The experimental design of sacrificing the mice on day 7 was used because the LTBP4-831 antibody is a chicken antibody that was expected to be recognized as foreign after 2-3 weeks.

[0156] Following harvest, the muscle was processed for analysis by snap-freezing in liquid nitrogen-cooled isopentane. The frozen muscle was sectioned and the sections were subjected to hematoxylin and eosin (H&E) staining.

[0157] Results of the experiment showed that, compared to PBS-injected mice, LTBP4-831 antibody-treated mice showed reduced central nucleation and reduced fibrosis (FIGS. 10A and 10B). Centralized nuclei are indicative of newly formed (i.e., regenerating) myofibers, and reduced central nucleation in the muscle of animals that were administered LTBP4-831 antibody provides evidence that the antibody mitigated muscle injury in the mice.

Example 9

Increased Inflammatory Infiltrate in hLTBP4/Mdx Mice Compared to Mdx Mice

[0158] Quadriceps muscles obtained from both mdx and hLTPB4/mdx mice were stained with F4/80 antibodies that recognize and bind to activated macrophages (shown as speckles throughout the muscle). The immunofluorescent staining showed an increase in activated macrophages in hLTBP4/mdx muscle compared to mdx muscle (FIG. 11A). hLTBP4/mdx muscle showed an increase in cleaved LTBP4 protein compared to mdx, while little LTBP4 protein was seen in wild-type and hLTBP4 muscle in the absence of injury or muscular dystrophy (FIG. 11B).

[0159] The results showed that there is an increase in inflammatory cell infiltrate in the muscle of hLTBP4/mdx mice versus mdx mice. The results also showed that hLTBP4/mdx muscle possessed increased cleaved LTBP4 protein relative to mdx muscle.

[0160] The disclosed subject matter has been described with reference to various specific and preferred embodiments and techniques. It should be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the disclosed subject matter. All references cited herein are hereby incorporated by reference in their entireties, or to the extent that they provide relevant disclosure, as would be ascertained from context.

Sequence CWU 1

1

1311624PRTHomo sapiensMISC_FEATURE(357)..(586)TP2E fragmentMISC_FEATURE(483)..(565)TP fragment 1Met Pro Arg Pro Gly Thr Ser Gly Arg Arg Pro Leu Leu Leu Val Leu1 5 10 15Leu Leu Pro Leu Phe Ala Ala Ala Thr Ser Ala Ala Ser Pro Ser Pro 20 25 30Ser Pro Ser Gln Val Val Glu Val Pro Gly Val Pro Ser Arg Pro Ala 35 40 45Ser Val Ala Val Cys Arg Cys Cys Pro Gly Gln Thr Ser Arg Arg Ser 50 55 60Arg Cys Ile Arg Ala Phe Cys Arg Val Arg Ser Cys Gln Pro Lys Lys65 70 75 80Cys Ala Gly Pro Gln Arg Cys Leu Asn Pro Val Pro Ala Val Pro Ser 85 90 95Pro Ser Pro Ser Val Arg Lys Arg Gln Val Ser Leu Asn Trp Gln Pro 100 105 110Leu Thr Leu Gln Glu Ala Arg Ala Leu Leu Lys Arg Arg Arg Pro Arg 115 120 125Gly Pro Gly Gly Arg Gly Leu Leu Arg Arg Arg Pro Pro Gln Arg Ala 130 135 140Pro Ala Gly Lys Ala Pro Val Leu Cys Pro Leu Ile Cys His Asn Gly145 150 155 160Gly Val Cys Val Lys Pro Asp Arg Cys Leu Cys Pro Pro Asp Phe Ala 165 170 175Gly Lys Phe Cys Gln Leu His Ser Ser Gly Ala Arg Pro Pro Ala Pro 180 185 190Ala Val Pro Gly Leu Thr Arg Ser Val Tyr Thr Met Pro Leu Ala Asn 195 200 205His Arg Asp Asp Glu His Gly Val Ala Ser Met Val Ser Val His Val 210 215 220Glu His Pro Gln Glu Ala Ser Val Val Val His Gln Val Glu Arg Val225 230 235 240Ser Gly Pro Trp Glu Glu Ala Asp Ala Glu Ala Val Ala Arg Ala Glu 245 250 255Ala Ala Ala Arg Ala Glu Ala Ala Ala Pro Tyr Thr Val Leu Ala Gln 260 265 270Ser Ala Pro Arg Glu Asp Gly Tyr Ser Asp Ala Ser Gly Phe Gly Tyr 275 280 285Cys Phe Arg Glu Leu Arg Gly Gly Glu Cys Ala Ser Pro Leu Pro Gly 290 295 300Leu Arg Thr Gln Glu Val Cys Cys Arg Gly Ala Gly Leu Ala Trp Gly305 310 315 320Val His Asp Cys Gln Leu Cys Ser Glu Arg Leu Gly Asn Ser Glu Arg 325 330 335Val Ser Ala Pro Asp Gly Pro Cys Pro Thr Gly Phe Glu Arg Val Asn 340 345 350Gly Ser Cys Glu Asp Val Asp Glu Cys Ala Thr Gly Gly Arg Cys Gln 355 360 365His Gly Glu Cys Ala Asn Thr Arg Gly Gly Tyr Thr Cys Val Cys Pro 370 375 380Asp Gly Phe Leu Leu Asp Ser Ser Arg Ser Ser Cys Ile Ser Gln His385 390 395 400Val Ile Ser Glu Ala Lys Gly Pro Cys Phe Arg Val Leu Arg Asp Gly 405 410 415Gly Cys Ser Leu Pro Ile Leu Arg Asn Ile Thr Lys Gln Ile Cys Cys 420 425 430Cys Ser Arg Val Gly Lys Ala Trp Gly Arg Gly Cys Gln Leu Cys Pro 435 440 445Pro Phe Gly Ser Glu Gly Phe Arg Glu Ile Cys Pro Ala Gly Pro Gly 450 455 460Tyr His Tyr Ser Ala Ser Asp Leu Arg Tyr Asn Thr Arg Pro Leu Gly465 470 475 480Gln Glu Pro Pro Arg Val Ser Leu Ser Gln Pro Arg Thr Leu Pro Ala 485 490 495Thr Ser Arg Pro Ser Ala Gly Phe Leu Pro Thr His Arg Leu Glu Pro 500 505 510Arg Pro Glu Pro Arg Pro Asp Pro Arg Pro Gly Pro Glu Leu Pro Leu 515 520 525Pro Ser Ile Pro Ala Trp Thr Gly Pro Glu Ile Pro Glu Ser Gly Pro 530 535 540Ser Ser Gly Met Cys Gln Arg Asn Pro Gln Val Cys Gly Pro Gly Arg545 550 555 560Cys Ile Ser Arg Pro Ser Gly Tyr Thr Cys Ala Cys Asp Ser Gly Phe 565 570 575Arg Leu Ser Pro Gln Gly Thr Arg Cys Ile Asp Val Asp Glu Cys Arg 580 585 590Arg Val Pro Pro Pro Cys Ala Pro Gly Arg Cys Glu Asn Ser Pro Gly 595 600 605Ser Phe Arg Cys Val Cys Gly Pro Gly Phe Arg Ala Gly Pro Arg Ala 610 615 620Ala Glu Cys Leu Asp Val Asp Glu Cys His Arg Val Pro Pro Pro Cys625 630 635 640Asp Leu Gly Arg Cys Glu Asn Thr Pro Gly Ser Phe Leu Cys Val Cys 645 650 655Pro Ala Gly Tyr Gln Ala Ala Pro His Gly Ala Ser Cys Gln Asp Val 660 665 670Asp Glu Cys Thr Gln Ser Pro Gly Leu Cys Gly Arg Gly Ala Cys Lys 675 680 685Asn Leu Pro Gly Ser Phe Arg Cys Val Cys Pro Ala Gly Phe Arg Gly 690 695 700Ser Ala Cys Glu Glu Asp Val Asp Glu Cys Ala Gln Glu Pro Pro Pro705 710 715 720Cys Gly Pro Gly Arg Cys Asp Asn Thr Ala Gly Ser Phe His Cys Ala 725 730 735Cys Pro Ala Gly Phe Arg Ser Arg Gly Pro Gly Ala Pro Cys Gln Asp 740 745 750Val Asp Glu Cys Ala Arg Ser Pro Pro Pro Cys Thr Tyr Gly Arg Cys 755 760 765Glu Asn Thr Glu Gly Ser Phe Gln Cys Val Cys Pro Met Gly Phe Gln 770 775 780Pro Asn Thr Ala Gly Ser Glu Cys Glu Asp Val Asp Glu Cys Glu Asn785 790 795 800His Leu Ala Cys Pro Gly Gln Glu Cys Val Asn Ser Pro Gly Ser Phe 805 810 815Gln Cys Arg Thr Cys Pro Ser Gly His His Leu His Arg Gly Arg Cys 820 825 830Thr Asp Val Asp Glu Cys Ser Ser Gly Ala Pro Pro Cys Gly Pro His 835 840 845Gly His Cys Thr Asn Thr Glu Gly Ser Phe Arg Cys Ser Cys Ala Pro 850 855 860Gly Tyr Arg Ala Pro Ser Gly Arg Pro Gly Pro Cys Ala Asp Val Asn865 870 875 880Glu Cys Leu Glu Gly Asp Phe Cys Phe Pro His Gly Glu Cys Leu Asn 885 890 895Thr Asp Gly Ser Phe Ala Cys Thr Cys Ala Pro Gly Tyr Arg Pro Gly 900 905 910Pro Arg Gly Ala Ser Cys Leu Asp Val Asp Glu Cys Ser Glu Glu Asp 915 920 925Leu Cys Gln Ser Gly Ile Cys Thr Asn Thr Asp Gly Ser Phe Glu Cys 930 935 940Ile Cys Pro Pro Gly His Arg Ala Gly Pro Asp Leu Ala Ser Cys Leu945 950 955 960Asp Val Asp Glu Cys Arg Glu Arg Gly Pro Ala Leu Cys Gly Ser Gln 965 970 975Arg Cys Glu Asn Ser Pro Gly Ser Tyr Arg Cys Val Arg Asp Cys Asp 980 985 990Pro Gly Tyr His Ala Gly Pro Glu Gly Thr Cys Asp Asp Val Asp Glu 995 1000 1005Cys Gln Glu Tyr Gly Pro Glu Ile Cys Gly Ala Gln Arg Cys Glu 1010 1015 1020Asn Thr Pro Gly Ser Tyr Arg Cys Thr Pro Ala Cys Asp Pro Gly 1025 1030 1035Tyr Gln Pro Thr Pro Gly Gly Gly Cys Gln Asp Val Asp Glu Cys 1040 1045 1050Arg Asn Arg Ser Phe Cys Gly Ala His Ala Val Cys Gln Asn Leu 1055 1060 1065Pro Gly Ser Phe Gln Cys Leu Cys Asp Gln Gly Tyr Glu Gly Ala 1070 1075 1080Arg Asp Gly Arg His Cys Val Asp Val Asn Glu Cys Glu Thr Leu 1085 1090 1095Gln Gly Val Cys Gly Ala Ala Leu Cys Glu Asn Val Glu Gly Ser 1100 1105 1110Phe Leu Cys Val Cys Pro Asn Ser Pro Glu Glu Phe Asp Pro Met 1115 1120 1125Thr Gly Arg Cys Val Pro Pro Arg Thr Ser Ala Gly Thr Phe Pro 1130 1135 1140Gly Ser Gln Pro Gln Ala Pro Ala Ser Pro Val Leu Pro Ala Arg 1145 1150 1155Pro Pro Pro Pro Pro Leu Pro Arg Arg Pro Ser Thr Pro Arg Gln 1160 1165 1170Gly Pro Val Gly Ser Gly Arg Arg Glu Cys Tyr Phe Asp Thr Ala 1175 1180 1185Ala Pro Asp Ala Cys Asp Asn Ile Leu Ala Arg Asn Val Thr Trp 1190 1195 1200Gln Glu Cys Cys Cys Thr Val Gly Glu Gly Trp Gly Ser Gly Cys 1205 1210 1215Arg Ile Gln Gln Cys Pro Gly Thr Glu Thr Ala Glu Tyr Gln Ser 1220 1225 1230Leu Cys Pro His Gly Arg Gly Tyr Leu Ala Pro Ser Gly Asp Leu 1235 1240 1245Ser Leu Arg Arg Asp Val Asp Glu Cys Gln Leu Phe Arg Asp Gln 1250 1255 1260Val Cys Lys Ser Gly Val Cys Val Asn Thr Ala Pro Gly Tyr Ser 1265 1270 1275Cys Tyr Cys Ser Asn Gly Tyr Tyr Tyr His Thr Gln Arg Leu Glu 1280 1285 1290Cys Ile Asp Asn Asp Glu Cys Ala Asp Glu Glu Pro Ala Cys Glu 1295 1300 1305Gly Gly Arg Cys Val Asn Thr Val Gly Ser Tyr His Cys Thr Cys 1310 1315 1320Glu Pro Pro Leu Val Leu Asp Gly Ser Gln Arg Arg Cys Val Ser 1325 1330 1335Asn Glu Ser Gln Ser Leu Asp Asp Asn Leu Gly Val Cys Trp Gln 1340 1345 1350Glu Val Gly Ala Asp Leu Val Cys Ser His Pro Arg Leu Asp Arg 1355 1360 1365Gln Ala Thr Tyr Thr Glu Cys Cys Cys Leu Tyr Gly Glu Ala Trp 1370 1375 1380Gly Met Asp Cys Ala Leu Cys Pro Ala Gln Asp Ser Asp Asp Phe 1385 1390 1395Glu Ala Leu Cys Asn Val Leu Arg Pro Pro Ala Tyr Ser Pro Pro 1400 1405 1410Arg Pro Gly Gly Phe Gly Leu Pro Tyr Glu Tyr Gly Pro Asp Leu 1415 1420 1425Gly Pro Pro Tyr Gln Gly Leu Pro Tyr Gly Pro Glu Leu Tyr Pro 1430 1435 1440Pro Pro Ala Leu Pro Tyr Asp Pro Tyr Pro Pro Pro Pro Gly Pro 1445 1450 1455Phe Ala Arg Arg Glu Ala Pro Tyr Gly Ala Pro Arg Phe Asp Met 1460 1465 1470Pro Asp Phe Glu Asp Asp Gly Gly Pro Tyr Gly Glu Ser Glu Ala 1475 1480 1485Pro Ala Pro Pro Gly Pro Gly Thr Arg Trp Pro Tyr Arg Ser Arg 1490 1495 1500Asp Thr Arg Arg Ser Phe Pro Glu Pro Glu Glu Pro Pro Glu Gly 1505 1510 1515Gly Ser Tyr Ala Gly Ser Leu Ala Glu Pro Tyr Glu Glu Leu Glu 1520 1525 1530Ala Glu Glu Cys Gly Ile Leu Asp Gly Cys Thr Asn Gly Arg Cys 1535 1540 1545Val Arg Val Pro Glu Gly Phe Thr Cys Arg Cys Phe Asp Gly Tyr 1550 1555 1560Arg Leu Asp Met Thr Arg Met Ala Cys Val Asp Ile Asn Glu Cys 1565 1570 1575Asp Glu Ala Glu Ala Ala Ser Pro Leu Cys Val Asn Ala Arg Cys 1580 1585 1590Leu Asn Thr Asp Gly Ser Phe Arg Cys Ile Cys Arg Pro Gly Phe 1595 1600 1605Ala Pro Thr His Gln Pro His His Cys Ala Pro Ala Arg Pro Arg 1610 1615 1620Ala218PRTMus musculus 2Glu Pro Arg Pro Arg Pro Glu Pro Arg Pro Gln Pro Glu Ser Gln Pro1 5 10 15Trp Pro317PRTHomo sapiens 3Glu Pro Arg Pro Glu Pro Arg Pro Asp Pro Arg Pro Gly Pro Glu Leu1 5 10 15Pro418PRTMus musculus 4Glu Ser Gln Pro Arg Pro Glu Ser Arg Pro Arg Pro Glu Ser Gln Pro1 5 10 15Trp Pro519PRTHomo sapiens 5Glu Pro Arg Pro Glu Pro Arg Pro Asp Pro Arg Pro Gly Pro Glu Leu1 5 10 15Pro Leu Pro643PRTHomo sapiens 6Phe Leu Pro Thr His Arg Leu Glu Pro Arg Pro Glu Pro Arg Pro Asp1 5 10 15Pro Arg Pro Gly Pro Glu Leu Pro Leu Pro Ser Ile Pro Ala Trp Thr 20 25 30Gly Pro Glu Ile Pro Glu Ser Gly Pro Ser Ser 35 407155085DNAHomo sapiens 7aagctttata ttataaatac aaagtaaaca tgaaaataaa acccaaacat agcagtgtta 60ttaaactctg gcctgtagca gtggctcaca cctgtaatcc tagcagtttg gaggccgaga 120caggtggatt acttgagacc tggagtttga gaccagccca ggtgacacag caagacctca 180tctctactaa aaataaaaaa aaattagcca ggtgtggtgg tatgcacctg tggtcccagc 240tacttaggat gctggagtgc gaggatcgct tgagcccagg aggtcaaggc tgcagtgaac 300tatgatcact cattacaccc cagcctgggt gacagagcga gatgctgtct caaaacaaaa 360caaaacgaaa aacaactctg gctagatgct attgcttgcc aagggtgcag tcttccattt 420attaaaagtg aaaattaggg ccaggcacat tggctcatgc ctgtaatccc agcactttgg 480gaggctgagg tgggtggatc acctgaggtc aggagttcga gaccagcctg gccaacatgg 540tgaaacctta tctctgccaa aaatataaaa gattagccat gtgtcgtggt gggtgcttgt 600aatctcagct acttgggagg ctgaggcagg agaatcactt gaacccagga ggcagaggtt 660gcagtgagcc aagattgtgc cattgcactc cagcctgtgc aacgagcgaa actccaactc 720aaaaaaaaaa aaaaaaaaaa aaacggaaaa ttaggtaata ctgcagattc attaatatca 780cagcagcact aaactcagtc ttcctctgtg ctgggctcaa gggaactgaa agggaagtaa 840cttgctatgt ggttcagtgt catttcatgc tgtgtcactg caccacttaa aatcttcacc 900cggagactat gtcccacaca tggggaaatc aatcaccgtc atattttaag tgcttgctgt 960gtgacagcca cgattacaat gactgttact ctacctctta ttctcactgt agtgttccca 1020gtgaagcggc ggaaccggca cagcctagtg gggcctcagc agctaggagg acggccagcc 1080cctgtccgac ggagcaacac gatgcccccc aaccttggca atgcagggct gctgggccga 1140atgctggatg agaaaacccc tccctcaccc tcaggtacgt ttctatctcg tggaaggttg 1200gggcagctgt ggggtccctg tgaccctctt ctgatcccta ctcttcccct caaggacaac 1260ctgaggagcc ggggatggtg cgcctggtgt gtggacacca taattggatc gctgtggcct 1320atacccagtt tctagtctgc tacaggtgct tggggaggga gtggcaggag gtcccagccc 1380tgttgatggg aagggcatgc ggtgagggtt ggtgatgtcc cctcgatcct acaggttgaa 1440ggaagcctct ggctggcagc tggtgttttc cagcccccgc ctggactggc ccatcgaacg 1500actggcgctc acagcccggg tgcatggtgg ggctttgggt gaacatgaca agatggtggc 1560agcagccacc ggcagcgaga tcctgctatg ggctctgcag gcggaaggcg gtggctccga 1620gataggtatg accccaagcc ttttccagaa ccctctgtcc tttaaattct actgcctgtt 1680aaaatgaccc accccataaa atcctcaaac ccataagaat tctctgctct attagatctg 1740tttgtgtcat tagaatgctc cagcccttca gaattctgta tcctgttaga attccctggc 1800ttcctagaaa aatccaccca catacaattc tccctccatc agaattccct gccctgttag 1860atctcttggt tttgttagaa tgcgctattc tgtgtggcca tgagaaatgt ctgacttggc 1920ccggtgcggt ggctcatgct tgtaatccca gcactttggg aggctgaggc gggcagatca 1980cttgaggtca ggagttcgag acccccttgg ccaacagggt gaaacccagt ctttatttca 2040aaaatacaaa aaaattagct gggtgtggtg gcacgtgcct gtaatcccag ctactcagga 2100ggttaaggca ggagaatcac tggaacctgg gaggcagatg ttgcagtgag ctgagatcgc 2160accactgcat tccagcctga gcgacagagt ggacagagtg agacaccatc tcaaaaaaaa 2220aaaaaaaaca aaaaaagaaa tctctgactt atggctgggc acagtaactc acatctgtag 2280ttccagcact ttgggaggcc atggcaggag gattgcttga ggccaggagt tcgaggctgc 2340cgtgagctat gtaagccatg attgcaccac tgcactccag cctggacaac agagcaagac 2400cctgtctcaa agccacagca acaaatctcg gacttattaa tctgtcccca aataaatctc 2460agccctcgta agaatcccct gccaccagtg gaggtttttt tgccttattg caaatctcag 2520tgctgttaga attccagacc gttttagaat cccatacccc atcagaaatc ttctggccca 2580ttttatcttc tctaattcct gctggaatct tcactttttt tttttttgaa atggagtcat 2640tctctgttgc ccagattgga gtacagtggt atgatctcgg ctcactgcaa cctctgcctc 2700ctggggtcac gcaattctcc ttcctcaacc tcccaagtag ctggggctac agttgtgtgc 2760taccacactc agctaatttt tatatttttt agtagagatg gagtttcatc atgttggcca 2820ggctggtctc aaactcctgg cctcaaatga tccgcccacc tgagcctctc aaagtgttgg 2880gattacaggt gtgagccact gtgcccagcc cctgatggaa tcttctatcc ttcaaggatt 2940ctgtggtccc actgaaccct ctggtccttg gagttcttcc tcccacctct cctcctccat 3000gaggcagggt tccagctgag ccctttttgc ccactgcagg ggtctttcat ctgggggtgc 3060ctgtggaggc cttgttcttc gtcgggaacc agctcattgc tacaagccac acagggcgca 3120tcggggtgtg gaatgccgtc accaagcact ggcaggtcag agttctggcc agcctggctg 3180cccccttccc agttttccag actgtacaga cccaggaagg ggttcacgtc tgcccccacc 3240cccaccccct aagcctggag gaagccagag aaccagcagc tggccagagc ctggggatgt 3300ctgtgataaa ggcctaagga gcaccaggga agccttcctg gaggaggtgc tgcagagccc 3360acatgaagca tgaatgggtt tgaaaaggag tagggaggat tgtcttggga ctgggtgaga 3420gagcaggtta ggggggatgc tgtagaagac aagaactggc ttggctcggt ggctcacact 3480tgtaatccca gcactttggg aggctgaggt gggaggatgg ctttgggaga aagacagaca 3540gaggcagaga aagagacaga gaggcagaaa accaggcaaa tagaaataga aaatcagaaa 3600gaggtgacag agaagggtag acagagtcaa accagactga accactgtgg cagatggggg 3660aactcagaga gataaatgga gatgaattag agtcatgtca gaagtacata gtggaggccg 3720ggtgcagtga ctcccgcccg taatcccagc actttgggag gccgaggcaa gaggatggct 3780tgagcccagg agtttgacgc cagcctggga aacataataa gactctgtct ctacaaaaaa 3840tttaaaaaat taaaacttta aaaagtacag agtccaggag aggccaagag tcagacagac 3900agatgcatca aagggaggaa gggagggaac aagacaggga caaaggcagg cctggggtgg 3960acggggctgg ggagcagtgg gtgggttctg gaggtggagg agagggccca tcctctgtga 4020ggggtcacca cggaaggaaa ggaatggaag ggctcccggc tgcagcctgt cctgccccac 4080ccccaggtcc aggaggtgca gcccatcacc agttatgacg cggcaggctc cttcctcctc 4140ctgggctgca acaacggctc catttactac gtgggtgagc agcagcctgt gtcccgggtg 4200cccgagaccc tcccctggga gaggggaagg gagggagaga

ggctggggca cttggaacaa 4260acccgctcca ccctccctgc ccaccccaga tgtgcagaag ttccccttgc gcatgaaaga 4320caacgacctc cttgtcagcg agctctatcg ggacccagcg gaggatgggg tcaccgccct 4380cagtgtctac ctcaccccca agaccagtaa gctatgaccc ggcttcccct gctgctgtca 4440cctgccagcc ccagccccag cctgcagctg tcccccaact tgtgtagcat gacccagagg 4500ggtttatcga ggggcggcag attcaactct ctctcatttt tttttctgag acagactctc 4560attctgttgc ccaggctgga gtgcagtggt gcaatcttgg ctcactgcaa cctccacctc 4620ctgagttcaa gcgattctcc tgcctcagcc tcccaagtag ctaggattac aggcgcccac 4680tgccacgcct ggctaatttt tgtagtttta gtagagatgg ggtttcacca tgttggccag 4740gctggtcttg aactcctgac ctcagatgat cctcccgcct cagcccccca aagtactggg 4800attacagacg tgagccaccg cgcccagcca gattcaactc tcatccagtc attcaacaaa 4860tatttactga gtatccctgt atataagcac gttctaggtg ctagatggtg gccaccctct 4920ccactagggg cagaatggac cattaggagt taatctttgt gtttctttcc cacctttgtg 4980attaaggcat gatgttcaca tgttcataaa acaacacaga tgcaggtttt acagcagatg 5040aacctgagtt ctcttacttg agacagtttt ttgttttgtt ttcttgacat caaatgcaga 5100atgggttaat ttttgagacg taattctcat accataaaat ttcccatttg aacgtgcaca 5160attcagcgga ttttagtata ttcacaaggt tgtacaacta tcaccatgaa caaattccag 5220agtatgttca tcacccccgt aagaaacccc ctgatcttta gcagtaactc cacatttctc 5280acttctgata ccctctagaa atcactaata tgctttctct ttttgtttga gacaaggtct 5340cgctctgctg cccaggctgg agtgcagtgg catgatctca gctcactgca atctctgcct 5400cttgggttca agcgattctc atgcctcagc ttcctgagta ggggaggatt acaggtgtgc 5460atcaccatgc ctggctaatt tttctacttt aagtagagac tgggttacgc cacgttggcc 5520aggctcaata tgcttcctat acctatggat ttgcctgttc tggacaattc ctgtaaatgg 5580gatcatacat tatatggtct tttgtgtctg catttttcac ttagcatatt tttttaaatg 5640gttagtgttt tctgggtctt aagatatcct tacctattct aggttacaaa gatcttctcc 5700tgaatttctt ctagaagatt tacagtttag tttttacatg gaagtctgtt ctatcagaaa 5760ttaaatttta tgtatggtgt gaagcaggga ttattctttt ttaaaaaaaa atagagacag 5820ggtcttgctc tgttgcccag gctagagtgc agtggcatga tgtgagttct ctgccacctc 5880cgccactcgg gctcaagcga ttcttctacc tcaacctcct gaacagcaga accacaggca 5940tgcatcacca cacctgtcta atttttgtat ttttttgtag agacagggtt ttgccatgtt 6000gcccaggcta ctcttgaact cctgggctca agtgatcctc acactttggc ctccaaagtg 6060ctggaaatac agacttgagt cactgtgctt ggccatagct gctgctgctg cttttctttt 6120ttttttaaag cagaaataag ttaataatac acctaacttc atgacacatt atcacctttc 6180ttctttgtaa ggcccttttc ttatttcttt tttttctttc tttctttttt tttttttttg 6240tcttttcctg agacagagta tcgctctgtc attcaaccca ggctggagtg caatggcgca 6300atctcagctc actacaacct ctgcctcctg ggttcaagca attctccaga ctcagcctcc 6360caagtagctg ggattacggg tgcctgccac catgcccagc taatttttgt gtttttagta 6420gaggcagggt tttgccacgt tggctaagca agttttgaac tcctgggatt ctcctctcgt 6480cgtctcccaa agtgctggaa ttacaggcat gggctgctgc acccggcctc tttcttattt 6540cacttactta ctcatttcct cctcatctcc cttcccgcca catgccacta ttatgtcatt 6600tttctttgtt ttttgagaca gtctcgcttc gtcacctagg ctggagtgca gtggcgcaat 6660catagctcac tgcagcctca ccccctgggc tcaagtgatc ctcctacttc agcctcttga 6720gtagctggga tcataggtga atgccatcac acccaactag ttttttaaaa atcttttgta 6780gagatgaggg tctcactatg ttgcccaggc tggcctcaaa cgcctggcct caagcaatct 6840tcctgcctcg gcctctgttc tctgttttac tttctctttc ctctcttatt tgctgtttca 6900ctgttacaat ttctgtctct gggcctctcc tcctttgacc tgtgcctttg tctccctgtt 6960cctccatttc ccacatctca tcaccatctt tttgtgtcct tccctctctc cttgctttct 7020gactgtgtct ctgttctgtg tctctttctt tctttctttc tttttttttt tttgagacag 7080agtcacattc tgtcatgcag gctggagtgc agtggcgtgg tcttggctca ttgcaacctc 7140tgcctcctgg gttcaagcaa ttctcatgcc tcagccttct gagtagctgg gattacaggt 7200gcgtactacc accaccagct aatttttgta tttttactag agacagggtt tcagcacgtt 7260ggccaggctg gtcttgaacg cctgacctca agcgatccac ccgcctcagc ttcccaaagt 7320gatgggatta cggcgtgagc caccgtgccc ggcctctcct tgctttctga ctgtgtctct 7380gttctgtgcc tgtttctttc tccctgccct ggtttctgtc tctgtggccc aggccctctc 7440ctcatccttg gcccctcacc aggtgacagt gggaactgga tcgagatcgc ctatggcacc 7500agctcagggg gcgtgcgggt catcgtgcag cacccggaga ctgtgggctc ggggcctcag 7560ctcttccaga ccttcactgt gcaccgcagc cctgtcacca agatcatgct gtcggagaag 7620cacctcatct caggtgagcc tctgtggggt gctccagtgc tgggagagac agctcagatg 7680ggagtgtgga gacaggagga tgagaatttc cactggggag ggacattgtg taggaagaga 7740gctctggcgg agaggattga cctgggatgg gactgtaatt gcagaagtga gagaatacca 7800taggggatca gtctggggaa gagtgaatct gtgtgtgttt gggaatccat caattcagca 7860acgatttacg gggcacccac catgtgccag gcatagggga tacagtgatg aacaagacag 7920gccaagtccc tgccctcgtg gagctgacat tctagcagcg atggcagaca ataaatctat 7980aaaaatggac atcaatggcc agctgcggtg gctcacacct ataatcccag aactttggga 8040ggccaaggcg ggtagattac ttgaggtcag gagttcgaga ccagcctggc caacatggtg 8100aaaccccacc tctaccaaaa atataaaaaa ttagccaggt gtggtggcac gtgcctgtaa 8160tccccgctac tcgggaggcc gagggaggag aattgcttga acctgggagg cggagattgc 8220agagagccca gatcatgcta ctgcactcca gcctaggcaa cagagcgaga ctccatctca 8280aaaataaata gataaaaatg caaatcaggc tgggcactgt ggctcatgcc tataatccca 8340gcactttggg aggccaaggt gggaggattg cttgaggcta ggagtgtgag accaacctgg 8400acaacaaagt gagacattgt ttctacaaaa aatttttaaa aaattagcca agtatggtgg 8460catgcacctg gggtcccagc ttcttgggag gctgaggtgg agggatcact tgagcccaag 8520agtcaggggc tgcaatcagc tatgattgca cccctgcact ccagcccagg caacaaagca 8580agactctatc tcataaaata ttaataaaat aatctaaatc aacaccaggc aatgataagg 8640gctatgaata aacatgaagc tgtgtgtggc tagagagtgt caagtcgctg gagaggggtc 8700attcagggaa ggcctgagga aggacctttg agcagaaata acagaatgag cagtgcagat 8760tggtagggac aagcattcag gccgagggaa caggcattgc aaaggctctg aggtgagagg 8820atgcctgagg aagtgcaggg agccacttgt gcctggaaca gagtaaatga gggggagaat 8880gggaggagat gagggtatgg aggtgacaag ggcaggagcc acagagggct ccgagcaggg 8940gagggacatg actagcttca ggtgttcaca ggctccacct ggctgcccgt gggagcacac 9000tactgggata ggacaggagc agggacctct gggaggggcg tgctgatacg gtccaggcag 9060gtgacgaaat ggaccaggac cggtgtgggg cagaggatag ggcaaggtga gatcaggctc 9120tggaacagtt ttggaggcag aggcaacagg gtttttaaca tttggaattc tggggaggaa 9180aggattctct gaaagggaag aactcagcaa gggctgaccc tcctgaaacg gggctgtcct 9240gaggctctgg acgggcaggc agcattgatg cctgcaccag gcctgacttc ctgctctcct 9300tgtgcccctc agtctgtgcc gacaacaacc acgtgcggac atggtctgtg actcgcttcc 9360gcggcatgat ttccacccag cccggctcca ccccactcgc ttcctttaag atcctggctc 9420tggagtcggc agatgggcat ggcggctgca gtgctggcaa tgacattggt gcctactggc 9480tcctggcctt cccaccccac tgaccccctt acctgacccc tgttgacctc cgctgattcc 9540cacttgcggc cacctgaccc aggagcctgc aacgattggg gtgtcctgat ccttgaggca 9600cctgagctcc actgactgcc acaacccccc agccctctct ggccctgccc aactctaaca 9660acctggggat gggactgggg tcttggggtg gtgggtttca tcagtgggga aggaagtctg 9720aggctgaggg aatcccagct ggccctgacc cctgcccctg cctggcccag gcccctacgg 9780tgagcgggac gaccagcaag tgttcatcca gaaggtggtg cccagtgcca gccagctctt 9840cgtgcgtctc tcatctactg ggcagcggtg aggacagtcc tgtccaacag ggagggagga 9900cagtcctgtc caacagggag ggaggtcagg ggagaaggca agatgctagc cagatcactg 9960aggccagaaa ggggtcccag ccaaggagca ttgaaggagc aaaggctggg agggaggaca 10020ggcctggtag gtttgtcttc tggtatcaaa ggtgtgacag gtgttggtgg gactgacctg 10080gcgcagtgcc agcccagtgc aggcagggcc aggttgaagg cacagggggt ggggtcaggg 10140tgggatgggg ggcccaggcg gagggggagg ggtgggatgg gggcccaggg ggagaggtcg 10200gggtgggatg gggggaccag ggggaggggt tggggtggga tagggggacc aggggcaggg 10260gtcgggatgg gatggaggag acccagggag ctgtaggagc cttgcttcag ctgggaaagg 10320ggcctcggag gatgttctgg atgaagggac tctgagcaga gacctagagg acaagtagga 10380aggagcagaa gaaagaaggc aggggaaggg ggccccagcc tgagggaact gtatgtgcag 10440aggctgagaa gggccaaata gggtcacatg ggaaggacac gtgggctcct gggctggagc 10500acagaacagg aggtgaggat ggggtgcaga tgcgggcggg ccttgtcagg ctgtggaagg 10560gctgaggctt tgtcctgtgc ggggagccgt ggccactgca tgggggatga aaggaggctt 10620gatgggaggc caggagccca gggaggaggc caggaggctg ataggaggtg ggggagcagc 10680tgggacgggc ctcaggtctt ccctgcagtg ggagcaggga agagcagaag ctctgggaga 10740ctccctgggt gtttggggct gcggtgtcca agagctgctg gacccttggg actggaactc 10800aaaagcaggc tagggatgga taaagattgg gatggcccct ggagaggcag gaactgcagc 10860cacagtggtg gggactggga cgaggaaggg tgagaaagcg agggtgacca cctcccccac 10920tgcacccccc agggtgtgct ccgtgcgctc cgtggacggc tcacccacga cagccttcac 10980agtgctggag tgcgagggct cccggcggct cggctctcgg ccccggcgct acctgctcac 11040tggccaggcc aacggcagct tggccatgtg ggacctaacc accgccatgg acggcctcgg 11100ccaggcccct ggtactccct gccccacccc aatcccgtcc caagccccac agcctcaccc 11160agaaccactc tccactgcca actgcttgat ctctctccca ggcccttgcc ctctgacccc 11220ttttcctttg accccctctc tgctccccat cccttcctgc ccttgttttt caacccctgt 11280ctcagcctct ggcccccatg cattgatctc tgcttcctct ctcctgtcct gaccctcggt 11340gcttgcactg caatgcaacc caggcccttg ccctatgacc cctgtcttgc cccctgaccc 11400tgcttccgtg ccccccagca ggtggcctga cggagcaaga gctgatggaa cagctggaac 11460actgtgagct ggccccgccg gctccttcag ctccctcatg gggctgtctc cccagcccct 11520caccccgcat ctccctcacc aggtagccac aactccactg ccccttctgt gcaatgaggg 11580gagaggggac agcatggtgt tcccggggac agagtggccc agctgccccg tgatgacgtg 11640cacttactgt ccttacttcc tcagcctcca ctcagcctcc agcaacacct ccttgtctgg 11700ccaccgtggg agcccaagcc ccccgcaggc tgaggcccgg cgccgtggtg ggggcagctt 11760tgtggaacgc tgccaggaac tggtgcggag tgggccagac ctccgacggc cacccacacc 11820agccccgtgg ccctccagcg gtctcggcac tcccctcaca cctcccaaga tgaagctcaa 11880tgaaacttcc ttttgaacaa cgcagctgcc atgatgcctt gggatgccct ggtcctgggg 11940gactcaggtg cctccctgat tcctgtggga accccgggtt cagggccagg gcctccttgg 12000aataaatggt tattgttact aggtccccac cttccctctt ttctggaagc caaagtcacc 12060ctccccaata aagtcctcac tgccaacatc ttgcttattc ttagcaggtt tgggactccc 12120caggaaaggg gtggggaaga tgtgggaccc aacccgatat atgcaaaatc aggaacatct 12180acctctcttg tttaagcaaa gggaggccag gcatggtggc tcacatctat aatcctggca 12240ctttgggagg ccagtttgct tgtgctcaga agtttcagac tagcctgggc aacataacaa 12300aaccccatct ctacaaaaaa atacaaaaat taagcaggca tggtggtgca tgcctgtggt 12360cccagcttct tgggaggctg aggtgggagg atcgcttgag cctaggaggc caaggctaca 12420gtgagccatg atcacaccac tgcactccag cctgagtgac agagtgagat cctgtctcaa 12480aaacaaaaca aaacaaaaaa ggtgttgcag gggaggaatg tgttggcttt tactctgcct 12540tcaggcatgg ctggatccgg ggcttcaaac actaattcag aatatctttt tttctttttt 12600cttttctttt ttaaagtctc actctgtcat ccaggctgga gtgtagtggt atgatctcag 12660ctcactgcaa cctccacctc ccgggttcaa gcaatcgcaa tcctcctgca tcagcctccc 12720gagtagctgg gattacaggt gtgcaccacc atgcccagct aattttttta tttttagtag 12780agacagagtt tcaccatatt ggccaggctg gtctcgaact cctgacctca ggtgatctgc 12840ccacctcagc ctcccaaagt gctgggatta caggcgagag ccactgtgtc cggcccagaa 12900tatcttttta tctcctaact tcacttacct ctggaataca tcttcaatca ggttttctct 12960ctgtggcaag gtgactctaa gcagctgctt agcaactctt tcttccctag caacagcaaa 13020aatcacaaga ctgattttca ttggcttgaa ttaagtcagg tggccattcc tgaaccaatt 13080actgtggcca gtgtgatgaa ggccttccat tattgcagcc tggatcatgt gtcctgctgt 13140atttttagta gaggcagggt ttcaccatgt tggccaggct ggtctcaaac tcctgacctc 13200agatgatcca cctaactcgg cctcccagag tgctgggatt acaggcgtga gccacctttc 13260ctggctggcc ttgggatttt ttttccccaa ataatgcccg ttcctacggc acttccttga 13320ggagattttc tgcatctttt ttccttgtgc caataaaaaa gggacagaaa gtggggacag 13380actaggagta gagaatacta gaacatgcta attctagaat tccatagttt ctggaatgcc 13440agagcttctg aaacatagta gagaggggtc tcgaacatta ggacatctcg gacacaagga 13500tattctggag tgctcatgga ttaacaatat tagagttctc ccctgcttat cagagaatcc 13560agaatataga agtttctgac aaaaaggacc tgaaaaatca ctgattctag aataggggag 13620tgtcaagggg agttcatacc catgaatctc caccggtagg aatatcttgc atgccaggat 13680gtctggaatg ctgagaatta taggatacag aaaggaacct ggattactag gaaatctaga 13740gaatgggaga gatcctggac tatccgccct tccagagcac tggaaggttt gtttgcgttc 13800caagaaatcc ataatggcag gagattccgg attatcagag aatctggaac acaaatggga 13860gacgtaaaag gtgagtgcct ctgaaaccgg ggtgttctga aatagctgtg cacctcaaac 13920cctaattttg tttttgtttg tttgtttttg agacagggtc ttgctttgtt gcccgggcta 13980gggtgcagtg gtgcaatcat ggctcactgc agcctcggcc ttctgggctc aagtgatcct 14040cctgcctcag cctcctgagt atttgggact acaggtgtgt gccaccacag ccagctactt 14100tttaagtttt tttgtagaga cattgtctca ctatgttgcc caggctggtc tcaaactcct 14160gggctcaagc cattctcctg ccttagcctc ccaaagtgct gggattacag gtgtgagcta 14220ccatgcccag cctcacactc tagaaaattt tttacatgcc aggatattca gaatattggg 14280ggatattggc atgttaggaa atctagtatg tagggggagg gcctggaagg tcaggaaatc 14340tagaatatgg tggtgttttg taatgctcac agatctagaa tattagagtc attttttttt 14400ccaggccgga gaatccagaa cgctcgtgtt gctgaaatgc tggtcattct attcttattt 14460catgtttaaa tttttattat tttctttatt tctttttttt gagacagggt ctttctctgt 14520tgcccgggtt ggagtgcagt ggtgtgatct cagctcacct caacctctgc ctcccgggtt 14580caagtgatcc tcccacctta gcctcttgag tagccgggat tacaggcgtg cgccaccatg 14640cctggataat ttttgtattc ttagtagaga cagggtttca ctgtgttggc caggctggcc 14700tgaaactcct gacctcaagt gatctgccct cccacctcgg cctcccaaag tgctgggatt 14760acagacgtga gccggcctta ttctggggga gggggtgggg ggggagagag agagagggag 14820agagagagga gaatttggga tgttagcaaa tctagaacac tgaagagctg ggttttttaa 14880atgctagaga tagtattatc ctagtatagt attaactctg tgtgtttttg tgcgtgagag 14940ggcatggggg gaggggtgga agattctgga atgcgggggg actagaactc tgagggattc 15000tgaagggttg agatgagtta ggattcaaga ggtgacatag acacgatcct gggagatagt 15060gacactgatg ggagggatgg ggagctgggg actccaaatt ctagggggag gggaggctaa 15120cgccggaagt tgcagtggtg agccagagga tgttgcctag caacaagcat tgaagatgcg 15180ctggatcccg gacagaaggg agaaatttca gcagcgcccc cagcaaatgc tccagccaca 15240gggtaggagg tggtgagggg ggaagcgggt agggatatgc tgtcctgcag ggtcatgtga 15300gcaggggtct tgggggttat acaaaaacag ggtcatggag tacagtcatg gggcagagcc 15360gggctctggg acagcccacg aatagctgtg aatggagtgt gagtgccgtc gtcacctgcc 15420ccagggactg tgtgtccctg gacggtgctg gacccagatt tctgggtgtc agtgtgggat 15480ggaggcatgg attgctgtag gtggcagtaa tggtgtgtag ccgtgtgagt cagcctgtgt 15540gtctcacagt gagcgggggt gaagggcttc cccgtcagtc ctgcacaccc tcctggattg 15600gaagaaggag caggagtggg gggtgggggg tgcaactgga tcagttgcca ttcttggtct 15660ggggtgggct ctgtggtcac ggcgtgtggc ctagtaccct gtgtgggtgg agcctgggat 15720ccacgaggtg ggggcggggc taacgctaca gaactgggaa gcttaagaat ccaactgctt 15780tgggatatgg ggcctggaac cccaaagcga agcaaacatg aaaggggtgg gcttgggatc 15840ctacatgtgg tcacgtccca gttttctgtg ggaaagggtg tggcctgaaa ctctggaaaa 15900agaggtgatt aggggcagag tgaagctctg agggtggtgc cttagggaga gaaggggctt 15960gtatttcaga gaatataggg tggagccttg aatttataat gatcttctca aagaattgat 16020cccttctcaa ggccctaggc ttcaggggtt ccaggctcac catctgcaaa agcttgctcc 16080ccgaagctct gtccctcagt gaacccagcc aggctctgcc cctgacccac aggatctgct 16140cccagggggt cctgggggct cctggctctg ccccctcctg cacctcactt attgccatcc 16200ccagagggta tcagaccccc ttccttgcct gagtctttga atgctcccaa gagctttgag 16260tctcaagctg ggcttgagac cctgagtttg aaggcttgaa gcctggaacc ccggtgtgga 16320cggggtttaa gggcccctgt ggcttgcagc tcctagtggt ggagactctt aggcaaggaa 16380gggatcggta ctctctttta tatagtttta tgtatttatt tattattgag atagggtctc 16440actctatcgt ccaggctgga gtgcagtgca gtgcagtggt gccatctcaa ctcactgcag 16500cctccactta ccaggctcaa gtgatcctcc tacctcatcc tcccgagtag ctgggactac 16560tggctcatgc caccataccc ggctaatttt tggatttttt tttttttttt tttttttttt 16620tttttttgag acagagtctt gctctgtcgc ccaggctaga gtgcagtggt gtgatcttgg 16680ctcactgcaa cctccacctc ctgggttcaa acgattctcc tgcctcagcc tcccgagtcg 16740ctgggattac aggcgcccac cactgcaccc agctaatttt tgtatttttt agtagagatg 16800gggtttcacc atcttggcca ggctggtctc gaactcctga cctcatgatc cacccgcctc 16860ggcctcccaa agtgctggga ttacaggcat gagccaccgc gcccggccta atttttggat 16920ttttaataga gatggggtcc tatgttgtac tatgttgctc aggctcacct caaactcctg 16980gactcaagcg atccacctcg gccttccaaa gtgctgggat tacaggcccg cgccagggca 17040cctagccgga actgggaact ctctaaggag aaagtctgca attctgggtg gtgggaggct 17100gctcttggga gcattcaaag actcaggcaa ggaagggggt ctgataccct ctgggggcgg 17160cgataagtgg ggtgcaggag ggggcagagc caggagcacc ctgggagcag agtttgtgga 17220tcaggggcag agcctggctg ggttcactga gggacagagc ttcggggagc aagcttttgc 17280agatggtgag cctggaatcc ctgaagccca gggtcttgag aagagatcaa ttctttgaga 17340agatccaatg tgaacttggg accctcagag gggcaggacc tgggggctgg tgcagggttg 17400gtgctccatt tgcagaatcc tcagtctctc tcgtggaaag gggtacccgt ggggggcttc 17460cagcttctac gccagcgagg gagctaaatt ctgaccgaat tctcccagaa ctgggagcag 17520agagctgagg actgccagat ggagtccagc ttaggggacc ctgcccccaa ccccgctccc 17580gtatccctcc catttttaag cacccctacg cctgggacct ctgttccacg agaaggttca 17640cggagccagt atccgagtcc taatttcccc ccaccgcgtg gggaactcga ggtcccccgc 17700gcccctagtc cggcacctgt ccctgctgcc tcctgattgg ccgcgcggcg agcgctggcg 17760gcgccgggct gtgattggcg ggaagttcgc agcccgtggc tggactgtgg agaaagtgag 17820tcggcctcgg gcgggggcgg gggcgggggc aggggcgggg ccggggctag cctgacccgc 17880tggacagacc gcccgcccgg agcgggactc ggcgcccgac acgatgccga ggcctggcac 17940cagcggccgc cgccccctcc tgctggtgct gttgctgccg ctcttcgcag ccgccacctc 18000cgccgccagc cccagcccca gccccagcca ggtcgtcgag gtcccggggg tccccagccg 18060cccggccagg taagccccct gcttccttgt gccccttcca cccaataagt ctggtggtcc 18120aggaggacca cggctttcgg attcagggga aactcgaacc cactgcttcg atgtggagat 18180gcaaagaggg cccttggatt tattaggcgc cctcaatttg taggggttag attcggggag 18240tactgagatt tttaggggaa agagtcccct ttattgtggt ggagaaggct aagtctccag 18300agaatcctgg ggttagttcg gggaaaggtc tctagtttat tggggcaggg ggtggggggc 18360tgagctctcc tagaatgata gagacgtgtg gggtcttcga gctaggatgg agcgccccaa 18420gtttcttggg cgcgtaagga ggaaaggtgt tgggggattc tggagggact ttatgaggcc 18480gctgagttgt cctggttttc taggatttgg gggctctgtg ttcatgaaaa gcgacctttg 18540ggtttttcga attggtcagg aagacataga ctcttgcgtt gatggtggag gggcttgtgg 18600ggagtggggt cgggtggggg agtcctcagg cttcagaacg gttggggatg ctcaagtttc 18660ctagaattag aggactctgg gattgaatga ggctccagtg atttcaccgc gagagatcca 18720ggattcccta tagatctggg ggctataggc gcccttcctg tctgcgggtg acgggactga 18780aggaagccgt ctgcccagca cccccaccca ccctccccgc ctggcggccc agcgctccgt 18840tacaaaggcc ccgggctcct ctcccgcctg ggtctctgcg aatgcgttta gtaacccgag 18900ccgcggcggg ggcggggccg ggaaggggtt aacctggaga aaaggcggga gggatgacgg 18960caagatcggg gatccccgag gctccccacc agatggcctc atcctccact cggccccacc 19020cacctgagag gggcccacgc gctggacacc cccctctctg caccccccca ctgctctcct 19080ctcggggtct gggcgcgcgc cctcgtctct agaccccctt agcctgggga taatggactt 19140gtctgggggg ccccttcatt gcgacgcact tgaaccggag ctggaagctc cgccactgag 19200accctctggg ctgggagatg tctgcaagaa cggcaccttt ctcctggtca ggcgggaaac 19260tgaggcccaa agaccaagaa acgctggctt ctggacacac

atcgtggaag ggcaagaacg 19320ggctagaact caggctctgg gattctcagt cctggactgt gactcccgtt atccccctcc 19380acctcagcac cctgctggac ccacagtcag agggaagagc cttccctccc cagctgccga 19440ggcctgtgaa aatggcgcca cctgtcggcc aggctcagga tggcgtctga gtcccggacc 19500gggatgtgcg ggagggcggg gttctagatt cccagacagt gcgggcttag aaatgctctt 19560agaaatcgag tcttttgttt ttgtttttgt tttttaatca cttttaaaag gctttaaaat 19620aacgtatttt ttcaataaaa tcgtacgcca aaatctcttc ataagacaaa agtacggttt 19680ctgtgccctt cagcccgaag tctaagccaa tttgcctccc attgtacaga tggagaaact 19740gaggcgtggg gagaagaacc tcgttagtca tatacctgtt tcaagccccc tcaggatgcg 19800tcttggtttc ccctccccga ttgccctcct ttgcagagtt ctggggtgct aggggcctga 19860gtgacttcca ctccactatt tatagcgttg ctgtttgtcg ctgctgcccg ggccagacgt 19920ctaggaggag ccgctgcatc cgaggtgggt tctggaagat ggagtatgag tagggggcaa 19980aagggaatag gaggagaggg gcagggagct ccccatccct cccctcatcc cagtgggaga 20040gctggatgca tttggtagag aagtacttgg tcccctcctt ccccacttag tccctggctg 20100tctccgaagc cttctgcagg gtccgaagct gccagcccaa aaagtgtgca ggcccccagc 20160ggtgcctgaa cccagtgcct gcagtgccca gtcccagccc cagcgtgagg aagagacagg 20220tgtccctcaa ctggcagcca ctgacgtgag tgggcagtcc ctcccctacc aaatcctccc 20280tcaggaactc ctagctttgc ccccgtttcc gctcctcctc ccttcccctc tccctctctc 20340tcccccctcc ctccccggct ctttcttttg ctatcagcct gtctgtccgt ttctatttca 20400tcccttgcct gcctatctca ggctcttccc atctctgcat tatttctgtc tctttctgtt 20460tctttctagt tacctgtctc ttttcctctc tctctttctc cctgtgtctc actgcctgcc 20520tctatgtcta agtctctctg ccccttctct ctttctctcc cccaaccccc atcatctctc 20580tttctctcag ggtctttgtt tctctcccac tagaggcctg gtccccataa ataggtgttg 20640tggggggagg gttgggcaga gccgctactg aaagacattt tcctggcatg gaggcccttt 20700ggtggggagg tcagtttaac ccggtgacag cagcttttcc gtcctctccc acccaggctc 20760caggaggcca gagctctact gaagcggcgg cggccccggg ggccaggggg ccggggacta 20820ctgagaagga ggcccccaca gcgtgccccc gctggcaagg ccccgggtaa gcacatccgc 20880ctttcctccg cctggggcga ggggggttcc gggccagata aagccgtctg gttcccacgg 20940tccagccgcc gcctacccgc cccccgttgt agctcagcac ccacccccag gacgaggccc 21000cctctaggga ccccagcgtc cggccgtgcg aggtgagccc gggacaggac cagacacagg 21060ccagaggcac tgacccgcgg gggtggggcc gggaagccag gcgtccgggc tccccgcggc 21120cgaagaggga gggcgctggc ccgttagaaa gctccgccga accagcccag acaacaaaag 21180cgattgtgcg ggttggcgcc tgcctgggca ccaaatgctc aagattgtgg ggcggctggg 21240ggccaaaggc ctcctcctgt ttcccgaatc ttccccctgc cctcctcccg ctccagctct 21300tgacccctag tctagaacac ccctcatctc aaacaccctc aaaaccctcc tcttgctgta 21360gccttcagcc cagatgtgac ccctccccct aaagtcttcc agatgtgagc ctcgggccag 21420atgttagtac ccccgcccac agcctccctt tatccattgt gacttctccc gccaggtgtg 21480gcgttctggc cagatgtggc tacatcttca catgtatccc ccccacctcc agcctcctgc 21540ccaggatcta gacgcccaat tcctttatgt gcccaggtgt agcgaccctt ctcccatccc 21600tcagatgtcc cacctggctg tccagatgta ccatgatagc cccctatcaa gatgaagccc 21660ctttctctgt gccccgggca gaagaggatc aactcttagc tgtctcccca aatgtggccc 21720ccactactct taatggattt cctctttatg gattcagctc tgtctggggg gaaacccgcc 21780cgcccccacc tgttcccttc cccgccgctc ccctacaggc ccggtccact tgttggtgcg 21840cggatgggga cagagggggc gccccgctca cccctgcgag tctagcgccc agcctgcgag 21900cctctggcta agcgcccagc cccacgcgcc cccgcgcggc cgccggggag ggagtggtga 21960ggaggggggg cctgagcggg ggcgcgggcg acctcccccg cgggcgggcg ggcgggtgcg 22020gccgggcccc tcgggcgggc tggggcggcg gcgcggcgga gcgcggcgct gcagccatgg 22080cgggcggcgt gcggctgctc tgggtgtcgc tattggtgct gctggcgcag ctagggccgc 22140agcctggact gggccggctc ggagagcgtc tccgcgtgcg cttcaccccg gtcgtgtgcg 22200gcctgcgctg cgtccatggg ccgaccggct cccgctgtac cccgacctgc gcgccccgca 22260acgccaccag cgtggacagc ggcgctcccg gcggggcggc cccgggggga cccggcttcc 22320gcgcctgtga gtgcggggtg gtggtcccga gagagcggct ccggggggga ggaggatccc 22380tggggatgga ggagacagtc ctccagggag agggagccca gattccatat gcaatagtgc 22440aagggaatat caggggctat ttgaggaagg gggccccaaa ttcctggctt ttggggttgg 22500gtcctgaggg ttccgatttt gcaagcaatg agggttctta gaggcctgtg atgtcccacg 22560tgagggaatt ggcgccagct ttcatgcttt gcgtcaaaat ggggatctca gaattgaggg 22620gcctgagaac ttttgggagg ggggctcgaa ttctgagacg ctgagtaagg agtccccggg 22680gaccaagcaa gagtctcagg accgcatggg ggacgtctca gtttctgtgt gtttgggtgg 22740gaaggttctg tatgggaatg cctgtgaggt ggggtactag agagaagaaa gttaatccga 22800agaactaaga gggagagggg acagagacgg gggttgtgtg tgtgtgtgtg tgtgtgtgtg 22860tgtgtgtgtg tggcggcggg ggtggggtgg gggtgtctcc gcaggacctg agttgcaggg 22920gtcccacgtg cgacagaaat ccagataaga gggcttacgg aaggggcgcc ccctgggggc 22980ggaggggaca ggaggtgtat gcaccaggca ctcctagaga tggggagcct tgggggttca 23040ggtgaggtgg gggagggcgc accacctgtt gttccaggat gcaaaagtgg gcagactctc 23100tgggatcggg ccttcctgcc ccctaccccg cagaccctat ggagtgggga gtgggggccc 23160ctggagcgga gaactcgccc agcctggccc ccagccagcc cagcccggcc ggcgtgagct 23220catctcccgc ctgagccccc gcccgctgcc actccctctc tcctcccctt cctccctctt 23280tctttcactc tttcccggcc cagccccaac gtgcctgtgc caggcgccat gcccaggcgg 23340gtgccaagcc cttgggggtg caaggagtgg catgtgaagt gggggctgac ctcaaaggga 23400cccctatgtc ctcaactccc cgcttggcca gggctgtggg gcatgacgtt ggctgtggcc 23460atctagtggc ccaccctggg tgtaggcacc cccagggagc tggcctgcgg gcctgcattc 23520aggccaagag aaggcagaga aatgcctctg gagcctggga aataccctca gacctggctg 23580gtttcccacc ccctccatca gagaccctta ccattctgca attttgattc ctagttaagc 23640ctctcctagg ccccactact caattaaaag cccccattag accaccctgg agtcatggcc 23700ccacactcct acctaaggga gctgagtttt tgctccaggc cctagacccg ctctccaacc 23760atggcaacag actttagaga ccactcctcc agtgaaattc cctctcattc ttccctccca 23820cctcccaaac tgtgcctttc cccagataac tctgtagtat tgtccagaag tcctgttctt 23880ctagctcacc cccttcccca ggaacttctg atcccattta tcttcagaga accccagggt 23940tggtcttgat aagtgggttc tcgcaagagg actccagaca ttgtgctcct tacaggcagc 24000cattaataaa aagcctttgg cacttaatcc ttagctggga ggggagggga ttccacagag 24060ggactcggcc aattgagcct cttaagtgct gatgacttcc aggaattcca cttcactatc 24120taaaccctgt tttcagcacc gtcaaactgg ttgtctccta ggcggcacta gagtcctgtt 24180ttctaggtaa ctgtccacaa aaggactcct gctgaaagga cgcctcagtt tcctctgagc 24240taggttcctc catcccagaa acctccagcc gtctttgaac tcgagaggac tgccctttag 24300tcgatctcct cccaggactc cagtcccttt atccttctaa acggaggtgg ctctctgcgt 24360cctttcctct ctacagttgt ggctcagaat cccacacgcg cctcccccgg ccgcctgcct 24420cctccctccc ctccgcacag ctgtctccag ctgttctctg cagccccggg agagagaggg 24480agggggtgcc ctcgcaggac agcccggcct cctttggctc aaaggtcccg gggctcccca 24540agggtccgga atgtggagcc tccgccctgc ccccgccgca cctctctctt tgtttacccc 24600gccgcacagc tggcagtgcc ccgcccagag gtggcctggg gcccagcgag ggcgcgcaga 24660ggggagtgga ggcgcgttcc cgctcgtggc tccgccccgg tgctactgga ggctgtaagg 24720ccgagctaga actctaaagc cccagccaga aagaagttgg gcggagacac agcgcggtgg 24780gcggaactag ggcacccgga cagcctggag gtggggtggg aggggcgtga acaagtgagc 24840cgggcgaatc agagtgcgga aaggaaggtg ggaggggcta gaggcagcag gttaagctcc 24900tggataggcg gggtttagaa tcccgcgggt agaaggtaat gtgagagggg ctacaaaggg 24960ggcacagcca gggggcggag gtaggacttc gtggaccaag cagagggagt gtgggcgggc 25020atagaatgcg aaggagacag agttgggcgg ggagttatgc cagggagtgg ttaaaatgtg 25080gtttgagtca atggaaggga tcagcattgg gtcggagggg ctggaacagc aaagggttcc 25140gtcggactac ggaatgggcg gggtcagcgc cgtctgggct ggtctggaac tccgtggact 25200cagccagaaa ttgggatccg agaggttgac atgaaagtga ataaacagcc tgagggctgg 25260ctgggctcac gcctgtaatc ccagcacttt gggagactga ggcagaagga ttgcctgagc 25320ccaggagttc aagaccagcc tggccaacat agtgagaccc cgcctctacc aaatttttaa 25380aaaacgtagc ccgatgtggt gcacgcctgt cgtctcagct acttaggagg ctcagatggg 25440aggatcactt cagcttagga ggtcgaggct gcagagccat aatcacgcta ctgcattcca 25500gcctgggcaa tagagcgaga tcctgccgac ttagtgggtg ggaccgtacc tctgatggct 25560gaacaactgg actgggccaa tgctgatgcc agaattgggg cggggccaca tgacagctaa 25620gggcggagcg acttagaaat gaatgatacc ttgagggagt agggacccca ggagaacctg 25680ccaggaatgg tggcgcccct gagtgtcctc gttctcctcc cagtcctgtg tcccttgatc 25740tgtcacaatg gcggtgtgtg cgtgaagcct gaccgctgcc tctgtccccc ggacttcgct 25800ggcaagttct gccagttgca ctcctcgggc gcccggcccc cggccccggc tgtaccaggc 25860ctcacccgct ccgtgtacac tatgccactg gccaaccacc gcgacgacga gcacggtgag 25920gaaagggtgg ccagagtccc ctccgacccc tgtcaagcat ttcactttgc ccctgaccct 25980catatttccc gccttcccga gcacctttgc ccagctcgcc ctccccgcct tgtctagccc 26040caccccgtaa gaacccgtgt agacatccgt ttgcccggcc gtgcctcccc taggcgtggc 26100atctatggtg agcgtccacg tggagcaccc gcaggaggcg tcggtggtgg tgcaccaggt 26160ggagcgtgtg tctggccctt gggaggaggc ggacgctgag gcggtggcgc gggcggaagc 26220ggcggcgcgg gcggaggcgg cagcgcccta cacggtgttg gcacagagcg cgccgcggga 26280ggacggctac tcagatgcct cgggcttcgg ttactgcttt cgggagctgc gcggaggcga 26340agtgagagga ggcccgtggg gaggggcccg gagcttgcct ccgcgcgggg gcgcgctcac 26400ccaacacttc cccgcagtgc gcgtccccgc tgcccgggct ccggacgcag gaggtctgct 26460gccgaggggc cggcttggcc tggggcgttc acgactgtca gctgtgctcc gagcgcctgg 26520gtaagcccca ggacgtcccc gaagtgctcg gagctgggga gtggtgacaa cctcaccgtt 26580cctcctactc tgccctagat aaacccagtt cacaaattgt agccacgcct accccattgt 26640ggaggcgact tccagtcctg agcttttcat accgctctgg gaccacccac cccattttct 26700gactttggcc actctgttct caccctgcct ttgtgccttg gccccccacc atatactttg 26760ggagtctcca atgttgccat ttcaactgcc aacctaaggc tgtccctgca cttaaactac 26820agccaacatc ttttagtccc tcccaccccg tcttcgtctc tgcccactcc attctcgctc 26880tgcccacctg tccctggccc acccctctcc tctcgccaca gggaactccg aaagagtgag 26940cgccccagat ggaccttgtc caaccggctt tgaaagagtt aatgggtcct gcgaaggtgc 27000aacggggcag gggtgggagg ggcttggttc tgggggcggg atttgcaggg atcaagttcc 27060tgactccacg gtgacctccc caaccctggc agatgtggat gagtgcgcga ctggcgggcg 27120ctgccagcac ggcgagtgtg caaacacgcg cggcgggtac acgtgtgtgt gccccgacgg 27180ctttctgctc gactcgtccc gcagcagctg catctgtgag caaccagcag ggagctgagg 27240ctgggtcccg ccctccctgc cctcagaagt cccagagcat cctggggcct ttaattccct 27300cggacccccc cagactcccg ggttcctctg tcagccttag agccccctca gaacttctca 27360gattcttata cagcttcagc atccctggac cacctttaga cctttcaagc cttttggatc 27420cagatccctc cagactccca gacttttttt tttggagatg gagtctcgct ctgtcgccca 27480ggctggagtg cagtggcgcg atctcggctc actgcaatct ctgcctcctg gtttcaagtg 27540attctcctgc ctcggcctcc cgagtagcta gaactacagg cgggcaccac catgcccggc 27600taaatttttt tgtatttttg gtagagacag ggtttcgcca cgttggccag gctggcctca 27660aacccctggc ttcaagtgat ctgcccacct cagcctccca aagtgctggg attacaggcg 27720taagccactg cgcccagctc tcccagactt tctggaatcc ttctcagacc cccaaatcct 27780ctcgtccccc tcaacgactc gactatcttc agatcttgag atccttctca gagtctctca 27840ttcaccactg acaccccatt gaggctccaa gcccttctca gacctccaga gcccactgct 27900ctccttcaga ccctctcaga cctctcccaa atgcccctcg cacccaccaa ccccccaccc 27960ccaaccccag aaccattccc ctctctccca aatccctcag tgctacagca ttcccagccc 28020cgccctgaag gatttcctcc ctgctcctcg cagcccaaca cgtgatctca gaggccaaag 28080ggccctgctt ccgcgtgctc cgcgacggcg gctgttcgct gcccattctg cggaacatca 28140ctaaacagat ctgctgctgc agccgcgtag gcaaggcctg gggccggggc tgccagctct 28200gcccaccctt cggctcaggt gagcccctgc ggcagtgcct agccctacgc gcaacacatg 28260tggcgctcat tctacgcccc accctccaac cctgagttca ctgccccaac ctgactggct 28320gggctccagc cttggccacg cagcagcctc tgagacccgc aggcctcaga ctggacagca 28380tccatggctc cacctccatc tgtagccaca gccacccctc cattcgtagc cacagctacc 28440ccggagctcc caagttagtt tttgtctcct gagcgtcaac gcccagtccc accctgtccc 28500tgaactttga ccaagtcctt ggcttctgag acactgcctt cagcttagcc ccaccccagg 28560catgcccctc cctgagacac ctccctggca ttctatcttc tgcttaaaac taaatctcac 28620aagggagcta tttcctagcc tccaactctg tccctgtaga cccaaccgga ccctgccctc 28680aaccctgttc ctaccaccat cccaaatgtg ggaaaacgct cttggcccca cctgtagcct 28740ctaagacatt ctactctttg gccaggacac caccccatcc cagcctccag ctcaaacccc 28800tgacactctc cagccaagcc ctgcccctag ccaaggccag agtctgggct ggccatcgtt 28860ttcttcccgc tctcttgtcc tctctctgtc tctcttacct attcccagag ggtttccggg 28920agatctgccc ggctggtcct ggttaccact actcggcctc cgacctccgc tacaacacca 28980gacccctggg ccaggagcca ccccgagtgt cactcagcca gcctcgtacc ctgccagcca 29040cctctcggcc atctgcaggt gagctggctc tggcagaagt gggtgccatc ttcaaggggc 29100tgccccagcc ccatagtgaa aggaggcaag agaggatttg ggctccactc gttgataccc 29160cttctttatc aggctttctg cccacccatc gcctggagcc ccggcctgaa ccccggcccg 29220atccccggcc cggccctgag cttcccttgc ccagcatccc tgcctggact ggtcctgaga 29280ttcctgaatc aggtttgcta gaaagaactg agggcattgg gcctgcagca gtggctcacg 29340cctgtaatcc cagcattttg ggaggctgag gagggtggat caccaggtca ggagttcgag 29400accagcctgg ccaacatggc gaaaccctgt ctctactaaa actacaaaaa ttaactgggc 29460gtggtggcag atgcctgtaa tcccagctac ttgggaggct gaggcaggag aatcacttga 29520acccaggagg cagaggttgc agtgagctga gatcgtgcca ttgcactcca gcttgagcga 29580cactccatct caaaaaaaaa aaaaaaaaaa gaattcaggg cattgatggg ggtattacag 29640gtgggattct ggggtaaaag actccaaggt gaagattcca ggttacagca aataggaatg 29700gtatgggcag agataagcgt ttgaagggtt gggtggtagt tagatcagga gctggagtca 29760cagttgggct cttctgtgtc aatcgagcaa gccatttaac ctctgagact cagttttctc 29820attggtaaaa tggggatggt tgttgagatg cctctgaagt gtctgacacc tagtaagtgc 29880tcagataaat acttatggta gataattatt tttcattatc taatattaga taattatttc 29940tcaggtaggg cactaagaat gtatctcagg cggagggttg gagagcaaac tattcaaagc 30000cagagacctt ggggtggcat gatgagggga ttcggccaag gatctgatga gaacgttcca 30060ggataaaaaa gatggagatc agaagaagac tgggcttgct tggggaggag acatccatga 30120aggtgtttta tggatgtctc cgggggtggg ggttttactg ggatgaaagg aacggaggat 30180tcagagatgg gggaaccctg gctgactgga ccccccaggt ccctcctccg gcatgtgtca 30240gcgcaacccc caggtctgcg gcccaggacg ctgcatttcc cggcccagcg gctacacctg 30300cgcttgcgac tctggcttcc ggctcagccc ccagggcacc cgatgcattg gtgagcaaga 30360cggagggcgc ggaaggaggc ggggcggggg gctttgcctg gtcaccttgt caccagcccc 30420ctccgtgtcc tcagatgtgg acgaatgtcg ccgcgtgccc ccgccctgtg ctcccgggcg 30480ctgcgagaac tcaccaggca gcttccgctg cgtgtgcggc ccgggcttcc gagccggccc 30540acgggctgcg gaatgcctgg gtgagaaatt tgccccaccc ggctccaggc ccaccccagg 30600gtctcgctcc tgctctcact ccagagcctc tccagccctc ccacgcttcc cctctcgggt 30660cccgccccag gactgctctg ccctggccct tggccctgcc cttccctgac ccgcctccac 30720ccagctccag cctccctttg accccacccc tacccagctc ccaaactgcc agtttctatc 30780ggggcctggt cgcaactcgt attgctccgc ccccacgccc aggccccgcc cttattggcc 30840acgcccctcc ctgactaact ccctccccca ggccccgcca ctgtcctgca actgcggcaa 30900ccaatctcct gaccgcgacc ccgattccaa ccctgccaca ccagagccct atccccaaac 30960tgctcctttc ttctctagcc cctaccccac cttcccttag cttggtcccc aaagctctcc 31020tttctgccct tgcgctacca aaccctgccc tccacaattg cctctctcac tgtgcccctc 31080tccggctgtc ctggccgggt ccccatcctg gctctggccc aagcttggtc ccgctcccgc 31140ttccctctac ccctgcctcc ttgcgtcgct tctcccgggg ctgtctgccc cagtcccagc 31200cgcctggtct gtgcctacag atgtggacga gtgccaccgc gtgccgccgc cgtgtgacct 31260cgggcgctgc gagaacacgc caggcagctt cctgtgcgtg tgccccgccg ggtaccaggc 31320tgcaccgcac ggagccagct gccagggtga gggcctggga ggggcagctg ggaaggggtg 31380tgagcggttg ggtagagcgc agtgatgagg gccagagaga ctgaacaata gggcaaagcg 31440agttgatttg gagacagagg ccaggctctc gagcagacgt gtggcctgat ggcagtagag 31500agagacctgg gatgcagagg ccaagtgatg ggaaacagaa aggctgagtc atgaaagatg 31560gagaagcaga atgaggaggg atggagatgt cagtaatcgg gtaaggggag cagagttatg 31620gaggaaaggg gagaaggagg ccttctcatg gggactacag agacagaacc agccaggcag 31680cttagtaggg attggtggag gatgcagagt cagatgatgg tgacaaggag gaatagagat 31740ggggtcacgg ggacagaatg ttggagggtg gaaagccaaa gtgacagagg tcagggaggc 31800agaggggaac aagtgacccc gggccccctg ccctgtgcag atgtggatga atgcacccag 31860agcccaggcc tgtgtggccg aggggcctgc aagaacctgc ctggctcttt ccgctgtgtt 31920tgcccggctg gcttccgggg ctcggcgtgt gaagaggatg tggatgagtg tgcccaggag 31980ccgccgccct gtgggcccgg ccgctgtgac aacacggcag gctcctttca ctgtgcctgc 32040cctgctggct tccgctcccg agggcccggg gccccctgcc aaggtgaggg tgctgagccc 32100agccctactc catcactgtt tgctgtggag actggagaga gattattgag gggcagagag 32160gcagagtgat ggggctcagg gatggagaac aggggctgag ggatggggac ctcactccag 32220agtcttctct cctttcaaca aaataaggca gtcctcccca cccctcctcc ctttttgaaa 32280gatactcttg tgcttatggg aaccctgagg agggggtcac ctgaggcagg gcaggcaaca 32340tggagttggt gccttagccc ccaccttagt agctggagag accattgaat ggggacacga 32400ggaaggtgtc tgtcttcctg ggaagaggga gcagcctgag gcaagtccag aaggcaggct 32460caagactgga atgctggggt gggtggtgat ggccatggga atggattcag gccccttcct 32520cagcctcatt ggtcccctct gccccagatg tggatgagtg tgcccgaagc cccccaccct 32580gcacctacgg ccggtgtgag aacacagaag gcagcttcca gtgtgtctgc cccatgggct 32640tccaacccaa cactgctggc tccgagtgcg agggtgaggc cggggaggga gggaggagtg 32700tggatgggtg aggggggagt tggaccactt cttcaaggcc accctctccc ctgcccccca 32760gatgtggatg agtgtgagaa ccacctcgca tgccctgggc aggagtgtgt gaactcgccc 32820ggctccttcc agtgcaggac ctgtccttct ggccaccacc tgcaccgtgg cagatgcact 32880ggtgagacca ggccctggct gtgaccttgg gcctgcatca tgacccccga cccttgaccc 32940agatcacaac tatgacctgg ccgtaacctc ctgacctgga cctcagtccc tcagtcccca 33000gagcctgtga ctcctgaccc tgacctggac cacaactctt gaccctgaat gtgactcctg 33060agacccaact tgacagtaac atttgaccct aaccatcacc cttgatgata gtccctgccc 33120ataccctgat agcaattgtg accctcatga ctctggccct gaatgtgacc tataactcct 33180gaatttgact gtgacatttg accctaatca taaccactaa ccatagcact gaccataacc 33240ttgactgtgt gactcttggt cctatctctt tcacagcccc tgcctcttct cagaatccct 33300tctctggaac ctggttgggt tcataatccc tgaccctggc ccctgacttg aggcagaatt 33360ctggaccctg actataactt ctgatcctaa ctggattcag attccagtca ctaactctga 33420cccatggctc agccgaatcc catccaatga tcctagttta taatacttga ctggtccctt 33480gccctagttg atttctgatc cctgtctgat ccctctcctg actccaaaat cctggcacag 33540gtagttccta gaaacctaga cccacaggac ttgcaaccat ggtccccgga acccgagaac 33600cttggtcagc cctacccacc tctgccatag agccctcccc cagcctccaa ctcatgagac 33660ttcccaccac ctcccccaga caccctactc caaggggatt ggtcgggtgt gtcccgagac 33720tggacccttt ctgaacaccc ccacccccca cagatgtgga cgaatgcagt tcgggtgccc 33780ctccctgtgg tccccacggc cactgcacta acaccgaagg ctccttccgc tgcagctgcg 33840cgccaggcta ccgggcgccg tcgggtcggc ccgggccctg cgcaggtgag cagcataggg 33900acccgccaga gagtctggga gtagggcctg ggttccaggg caaagccggc tggaaaggtg 33960gaggcgggac caaggcgctg tgggaggagc ttagaaacct ggcattggtg ggggcggggt 34020tactgcgatg tgggcggagc ttgtctggga ggccgggtcc cgtgactccg cccaatctcc 34080cgcgtaccct agacgtgaac gagtgcctgg agggcgattt ctgcttccct cacggcgagt 34140gcctcaacac tgacggctcc tttgcctgta cttgtgcccc tggctaccga cccggacccc 34200gcggagcctc ttgcctcggt tcgtacccgg gctgatcctg gccccggaaa gggtgggctt 34260agggcaggaa aaggcgggac ggggagaaga gggcgaaaag gggaaaacga gtttttagcc 34320ggggtattcc agcaggatca gggggcagct ggtgggagtc

tcgaggcagt gagggggggc 34380ggggcgtgga gatgaaaggg ccgagtctgg gtatttggac cgtgattgta aagaagctgt 34440tctaaacccg tcggggggcg gtgtttgcag ggagggaagt agcgtgaggc aggttgggga 34500aggcgtgaga ggcctaggag agccgagggg cggtggaggg gtgtggccta gaatgttagg 34560cggagcggga ggtgggccgg gccttcggac gccctgtccc gcagacgttg acgagtgcag 34620cgaggaggac ctttgccaga gcggcatctg taccaacacc gacggctcct tcgagtgcat 34680ctgtcctccg ggacaccgcg ctggcccgga cctcgcctcc tgcctcggtg agaggccccg 34740ccccggcctg atccctcctc ccttcgactc cccgactcgc cgattggcct cccacctctg 34800tctttcctcc tccgcttctc ccctcccctt acctctttcc cccgcctcct ctcctagcct 34860ccccaactct cctctacccc aatcttctcc tgccctctcc tctgcttccc cggcctcccc 34920cttctgactc tcctctcccc tctttgtatc ccccatcttg cctccctgct tcccacatcc 34980gaccacccga cctctctcct cagacgtgga cgaatgtcgc gagcgaggcc cagccctgtg 35040cgggtcgcag cgctgtgaga actctcccgg ctcctaccgc tgtgtccggg actgcgatcc 35100tgggtaccac gcgggccccg agggcacctg tgacggtgag cctgccccca cccgccttcg 35160ctagcgcttg caacgcggtg ctggaggctg ctcccttggg gactgaggag gggcgccctg 35220cttcccagac ttaggcggag ggaaagaaca ccctctcacc gtatctctgt agtggaaata 35280agccgccacc gtgtccatgt attttcttgt gtcaggatca cggccaagcc tcccttccag 35340ccgcagtcca ttccccctct gcagctgaag cccggtccac attttaggct atgcccccag 35400taagacaccg ccccaaaact gttaggcccc gccccttcca atcggcctct ggattaaaac 35460cccctcttca ggccccttct cttcctaaca gaagtttgga cgtgcccttt ccgcgccctc 35520caccagtcct acttccagcc ttccctccaa agaggcccaa tcccggtggc cctaggcccc 35580attctttccc aatgagaaat tcccaaggtg aaattctcct agcattggcc cccgcccgtt 35640taagctctgc ccttccttgg tctctctaga cagggctttc cattcgctcg gatggctcca 35700gtctctcgaa cacttaggcc ctcccttcct atctttgctc cgcccacaga cccgcccctt 35760gccttttctt actttccagg ccttccctcc cgccccgctc tttcacccct cccgggtcag 35820gctccagcga ggcaggaggg tggggctaat cttccataca gtatatattt ttttgtgtcg 35880gcgggggggg gggggcggtg atggtgtgtg agtccgcatc ttgtggaaca catgaaacaa 35940aacatctgtg ggctgccgtt gactctgcta gacctctgac tcatggaaat ctagcttcat 36000aagatctcat tcattaattc cacaagaatt cactaagcac ctactctatg ccagcgtctg 36060gaaaaggtaa taagagcaac aggaaataag tcatataaaa acccctgcct tcctggagtt 36120attgtggggt aataaatatg taaataaatt caagatttat acagcaggcc aggagctgtg 36180gctcatgcct gtaatcccag cactttggga ggccaaggcg gatggatcac gaggtcagga 36240gatcgagact agcctggcca acatggtgaa accccgtctc tactaaaaat acaaaaatta 36300gctgggcatg gtggcatgcg cctgtagtcc cagctactca ggagactgag gcaggatact 36360cgcttgaacc cgggaggcgg aggtggcagt tgagccgaga tcgcgccact gcactgcagc 36420ctcggcgaca gagtgagatt gtctcaaaaa aaaaatttat acaacaaaaa actggggggc 36480accttactat atgttgggca ctggagatgt agcaaggaac aaaatagaca caaatccctg 36540ctattgtaga gtttgtattc tagagaggcg acagttggca taccaataaa tacatacgta 36600taacatcagg tttaggaagg aaaacaaagc aagacaaatg ggacagagat gacagagcag 36660tggatggagg agtgctagga gggcttgacc tagacaccag acagaagcga gggaggcagc 36720catgcagaga gctgagggga gactgttcct ggcagaggga agagccagtg caaaggctct 36780gaggcaggac catgcttttg agaaatggca gtgaggactt gagagttatc aactatgcta 36840ggtgtggtgg cacaagcttg taatcccagc tactcaggag gctaaggtgg gagaactgcc 36900tgaacccggg aggttgaagc tccagtgagc catgatcctg tcactacact ccagcctgag 36960caacagagca agaccccatt taaaaaaaag aaaaaaaagc tggatggggt ggctcatgcc 37020tataatccca gcactttgga aggctgaggc agctagattg cctgaggtca gaagttcatc 37080accagcctgg ccaatatgat gaaaccccat ctctactaaa gaaaaaaaaa aaagatagtg 37140gctgggcgtg gtggctcaca cctgtaatcc taggacttga ggaggccgag gtggacagat 37200cgcttgaggt caggagttcg agaccattct ggtcaacatg gtgaaatctc atctctacta 37260aaaatacaaa aattagctag gcatgatggt gcatgcctgt agtcccagct gctctagaag 37320ctgaggtaga attgcttgaa cctaggaggc aaaagttgca gtgagctgag attgagccac 37380tgcactccag cctgagtgaa agagcgagac tccgtctcaa agaaaaaaca aagttttcaa 37440cattgttgat cttcagaagc tcaggctcct agaataccag attgctaaag acttcttagt 37500cttgggcacc ggaagtggtg ttagaacttc tgaattcagg cctttgactc ccctttcatc 37560tcctccacac tctgcagatg tggatgagtg ccaagaatat ggtcccgaga tttgtggagc 37620ccagcgttgt gagaacaccc ctggctccta ccgctgcaca ccagcctgtg accctggcta 37680tcagcccacg ccagggggcg gatgccaggg tgggtgtcca tcaggcatcg ggtgagatgt 37740ggagatggta gaaggtccag aaatggcctg actgtctggt ggttgcagat gtggacgaat 37800gccggaaccg gtccttctgc ggtgcccacg ccgtgtgcca gaacctgccc ggctccttcc 37860agtgcctctg tgaccaggtt acgagggggc acgggatggg cgtcactgcg tgggtacggg 37920acttcaggag gtggatggga ccaaaggggg tgggggaggt tggtcaggcc ctgtccctcc 37980ccatatatct gaacaaatgg gaattttcgg gttgtggaat ttagactttg gaatataaga 38040tcatcttcat gccaggcacg gtggctcacg cctgtaatcc cagtactttg ggaggccgag 38100gcgggcagat cacttgaagt caggagtttg aaaccagcct ggtcaacatg gtgaaacccc 38160gtctctacta aaaatacaaa aattagccgg atctggtggc aaatgcctgt aatcccagct 38220actcaggaag ctgaggcaca agaattgcct gaacccaaga ggtggaggtt gcagtgagcc 38280aagattgtgc aattgcactc cagcctgggt gacagagtga gaccctgtct caaaaaaaaa 38340aaaaaaaaaa aaaaaatcag aactgttgta gtggctggtg acagaaacct gacttaatca 38400ggttttattt ttgtgtgtgt tcttttaaaa atgtataaag tataaatgta taaagtacta 38460atcttaagtg ttcataaaca ttaatctttc ctaacatttt atgaggaaaa tttctaaaca 38520caaagcaaat tgagagaatc atagaatgaa cacctaccta ctcatgatct agattatatt 38580atcattttat tacacttgct tcctcacata tctatccatt aatccatcta attttttgga 38640cagagttaaa agtaaattgc aggcaccagt ctgcttcccc ataaattctt caatatgcat 38700atcactaacc agaattcaat atgtgtttac caatgtattc ttctcttctc tctttttttt 38760ttttactttg aggtggggtc ttgctctgtt gcccaggctg gagtgtggtt gtttgatcat 38820agcttactgc agcctctaac tcctgggctc aagccatcct ccctccagaa ctgagcttcc 38880gagtagctgc taccacaggc acacgcaacc acgcccagct aatgttttta atttttgtag 38940agatgagttt tttttttttt tttggagaca gagttttgct ctagttgtcc aggctggagt 39000gcaatggcat gatcttggct cactgcaacc tccacctccc gggttcaagc aattctcctg 39060cctcagcctc ccaagtagct gagattacag gtgcccacca ctatgcccag ctaatttttt 39120gtactttgag tagagatgga gttttgccat gttggccagg ctggtcttga actcctgacc 39180ttaggtgatc cgcccaccgt ggcctcctaa agtgctggga ttataagcat gagccaccac 39240gcctggcctg tagagatgag ttattgctct gttgcccaga ctggtctcaa actcctggct 39300ttaagcaacc ctccctcctt ggcctcccaa agcactggga ttacaggcat gagccattgt 39360accctacaga tattttcatt caacgttcaa tttatataca gtgaaatgca gcaatcttaa 39420ttatacattc tgtaaatttt cacaaatgca aacacaacag gttttatttc tttaaaggga 39480attaaaacta taaagtcttg ggatatattt gaactccagg cataactgga tccaggaatt 39540ttaacaaggc tatttctatc ttctctgagt tctgctttct tctattgcat gattttcagg 39600cagattattt ttcacaatga tgaaggtggc cctagaacct ctgggctaac atctccagtg 39660ggccacccga gagctaaaaa gggaggtttt tttttcaata tttctagcaa aagcgccagg 39720cctggctttg attgacccag catgatcact gcctatgtct gaaccagaga aatgccgtca 39780tctgtttggt cattcctgga acttgtgccc acctctcaga gtagatatag ccctactcaa 39840agaacaggat tgaaaataga ggagcacagg gttcccaagg gaaattcaag gtttctcact 39900agaagaaaaa cagatgatgg gatctgggcc attaaatata cacattatat ttgaaagctg 39960agactttcgg acctttggaa tcatagaagc ttataaccac tgagtccctc tcccctgttg 40020tctcctgctt acagatgtga acgagtgtga aacactacag ggtgtatgtg gagctgccct 40080gtgtgaaaat gtcgaaggct ccttcctctg tgtctgcccc aacagcccgg aagagtttga 40140ccccatgact ggacgctgtg ttcccccacg aacttctgct ggtgagactg atgtgtctat 40200ttaactgatg gcggctggcc ccatgggaaa atcacgtggt ctaatcattc ctgatgtgga 40260cagctaccat cagctaaata ctgttgtttt aaacatcaac aaaagacaca taagttaaca 40320tgggtagtga gactgtgtca ggagaattag accctggtcc tgactctacc agattctttc 40380attcaacaaa tgttcacagg gtgtgcactg tgttcaggcc atcttctggg cactgagaac 40440atagtagtga ccagaaggga tcactgtctg tcctcaaggg gctcacaagc caatggggca 40500gacagagata tcaccagata gtgacaaccc agagaaatca acaagactgt gacggggaaa 40560gcccaggggg gttttggagg aggcgcctgg cccagcatga gaagaggatt agggagttct 40620tcctgtagga gacgacatct gaactgagag ctgtgggatg aatagaaatg agccaggccc 40680gatgagtgag gagggcattc tgggcagagg acacagcaag ggcaaaggcc tggcaaagcc 40740agagagcatc tggcatgtga gaagaactga aacaggttca acatggcatg atttagagag 40800caaaggaagg ggtagggaga gatggggcca gggaaagagt caggtgcccg atcacactga 40860cttatcacag taagagagca ctgcggtacc gtggaagggg tttcggcgtt ttttttttga 40920aaattttttt taaatgtttt ttttttaaga cagggtcgta ctttcaccca ggccggagtg 40980cagtggcgtg atctcagctc actgcaacct ccacctcctg tgctcaagga atcctccaac 41040ctcagcctgc tgagtaactg ggactacagg cacatatcac cacaacagct aatttttgta 41100ttttttgtag agatgtggtt ttgtcatgtt gcccaggctg cagtattttt ttttttttaa 41160tttttaaatg ttacatattt aggctaggat tggtggctga aggccataat cccagctctc 41220tgggaggcca aggcgggagg atcacctgag gtcaggagtt cgagaccagc atggccaaca 41280tggcaaaacc ctgtctctac taaaaataca aaaattagct gggtgtagtg gtgcacgcct 41340gtaatcccag ctattcgaaa ggctgaggca ggaaaatcgc ttgaatccag gaggcggagg 41400ttgtgggatt gcaccactgc actccagcct gggtgagaga ggaagactcc gtcccaaaaa 41460aaaaaaaaaa aaaaaagcta tgtatttatt tatttttaat aatttccatc tttactttag 41520attcagggga tacatgtgca ggctttttac ctgggtatat ttcgtgatgc tgagctttgg 41580gatacaaatg atcccgtcac ccagatagta agcacagtac ccaacagcca gttttttttt 41640ttctttgaga cggagttttg ctcttgttgc ccaggctaga gtgcagtggc gtgatctcag 41700ctcactgtaa cctccacctc cctggttcaa gtgattctcc tgcctcagcc tcctgagtag 41760ctgggattac aggtgtccgc caccacgccc agctaatttt ttgtattttt agtacagacg 41820gggtttcatc atattggtca ggctggtctc gaactcctga cctcaggtca tccacctgcc 41880tcggcttccc aaagtgcagg gattacaggc gtgagccacc atgctcggcc caacagccag 41940tttttcaacc cttgtacctc tgtccctccc ccatctagtg gtccccagca actattgtgg 42000gcatctttac atccatgagt acccactgtt tagctctcac ttgtaagtga gaacatgtgg 42060tatttggtct tctgtttctg cattaatttg cttaggataa tggcctccag ctgcatccat 42120gttgctgcta aggacatgat ttcattcttt ttcatggctg tgtagtattc atggaagggt 42180tctaagcagg aaagatagaa tcagattttg aaacctccct ctggccgcca tgtgaaggtg 42240attgaagcgg gtgatatgga ggctgggagc tcagggaaca ggctggggca ggggcctgga 42300caggagagaa cagggctgga ccaaggcagg ggctgtggaa ggggaggaga aggtggtggg 42360agaaaaaccc aagaggccat gtggacaagc tgtggatgtc tgggtgggga agctgtgtcc 42420aagacaaggc ataggttttt tgtttgtttg ttttgtgaca gagtctcgct ctgtcgccca 42480ggctagaatg cagtggtgtg atctcggctc actgcaactt ccgctcccgg gttcaagcga 42540ttctcctgcc tcagcctccc aagtagctgg gattacaggc atgcgccacc acacccggct 42600aattttttct atttttagta gagaccgggt ttcaccatgt tggtcaggct ggtctcgaac 42660tcctgacctc aagtaatcca accgcgtcgg cctcctgaag tgctgggagg acaggcagga 42720gccactgcac ctggcgacaa attgtaggtt ttgagatgaa gactcagcca gtttgccaca 42780cactggataa gagacccaga gaggcatcca ggaagccagg gaagttccct caccacccac 42840ccaagctgtt agctgcagtg acgggaaagt gtgaggtggg gaggcaagag atgcagaaat 42900gacaggaggt gacagtggga gaaagagaaa cagtgacaga ggagcgtgag aggtgtggag 42960tctggttctg ccactgatgg ctgccaccct ctgtttccct atctatgcca gcctcagttt 43020ccccatctat gatagtggcg gggctgggga ttcagcccac actgggctaa agctccttgt 43080ctccccaggc acgttcccag gctcgcagcc ccaggcacct gctagccccg ttctgcccgc 43140caggccacct ccgccacccc tgccccgccg acccagcaca cctaggcagg gccctgtggg 43200gagtgggcgc cgggagtgct actttgacac agcggccccg gatgcatgtg acaacatcct 43260ggctcggaat gtgacatggc aggagtgctg ctgtactgtg ggtgagggct ggggcagcgg 43320ctgccgcatc cagcagtgcc cgggcaccga gacaggtggg catgggctga tggggacaca 43380gggctgaggg cttgggtgga aatactgggt ggggtgtggg cctgggacag gggacacttt 43440tggacagggc cttgaggtac tagtactgtc agggcaaggg cgagctgcca ggcaggtggg 43500catgggcaga cataaggctg agaggtgggc actaacaggc acagggccag agggactttt 43560gtgacaagtg ggcacgagca ggtcagggct ggggctgggg ctctggtgtc ctggctcagg 43620cttgtctctg tgtgtagctg agtaccagtc attgtgccct cacggccggg gctacctggc 43680gcccagtgga gacctgagcc tccggagagg tgaggccagc ctttgaccct ccaccccact 43740cagctctgag gcccagcttc gtctcttcct gttttctttg cctctgtctc tcaccctttc 43800tgtttctctg tatctgtctc cccgacccca cccatactct gtctctttct ttcttttctt 43860tctttttttt ttttttctta agatagagtt ttgttcttgt cgcccaggct ggagagcaat 43920ggcgagatct tggctcactg caacctttgt ctcctgggtt caagcgattc tcttgcctca 43980gcctctggcg tagctggcta cagacactag ccactacgcc tggctaattt ttttgtattt 44040ttagtagaga cagggtttca ccatgttggc cagattggtc tcgaactcct gacctcaagt 44100gatccgccca ccttagcctc ctgaagtgct gggatttcag gcatgagcca ccgctcctgg 44160cctctccatc tttctttccc tgtctctact tcttggtcta tcaccagctc tgtctctgtc 44220ttcccacgtc atgccctcac acactccacc catccagccc gcccccatct ctctctctgc 44280ttttcgcaca gacgtggacg aatgtcagct cttccgagac caggtgtgca agagtggcgt 44340gtgtgtgaac acggccccgg gctactcatg ctattgcagc aacggctact actaccacac 44400acagcggctg gagtgcatcg gtacaagccc cacctccccc aacccccggc aactctctcc 44460aacccctagc cttgccagct cccctctgga atgtggccac caccagcggg aagtctttcc 44520tggagtctag actccatcca tcacactgcc aatgtgctgg gaagagaaat gggaaagggt 44580ggggagagtt gaaggggatg cctcttaatc atcctctccc tagacaatga cgagtgcgcc 44640gatgaggaac cggcctgtga gggcggccgc tgtgtcaaca ctgtgggctc ttatcactgt 44700acctgcgagc ccccactggt gctggatggc tcgcagcgcc gctgcgtctc caacgagagc 44760cagagcctcg gtaaccccgc ccacgccatc caggccctcc ttcccttggc tcggcctcac 44820acccgcaccc gggccacacc tttgcgacgg ccacgccctc cgaaggccac gccccatgct 44880cctggctcga ccacgcccca ctgagccctc actcagtctc tgtcccactg tctgtctctc 44940tgaggcgagc tggctaggtg gttaaaggca aaagttttag ggcaaccttt gcatgttgcc 45000tcttggactc caggtttctt tctgcacact gggtgaatag cccctacctt atagggtggc 45060tgtgaggaat tttatttaat tttatttatt tattttttga gacggagttt cgctcttgtt 45120gcccaggcta gagcgcagtg gcgccatctc agctcactgc aacctccacc tccggggttc 45180aaacgattct cctgcctcag gctcccgagt agctgggatt acaggcatgt gctaccacgc 45240ccagctaatt ttgtattttt ttctttagta gagacagggt ttctccatgt tggtcaggct 45300ggtctcgaac tcccgacctc aggtgatccg cctgccttgg cctcccaaag tgctaggatt 45360acaggtgtga gccaccacac ctggctgatg aattttattt tattttattt tatttttaat 45420ttttaatttt tagttttatt atttattttt tactaagtac cacatgagtg ctgcctgtta 45480ttatttatct gcatctctag gtctctgtct ctttccagct gtttgtggat ttctgtcttt 45540ggggttttct ctgaatttct gacaccctct ggatctttgt tttcaggtcc ctttctcctg 45600cctctgtatc tttgttttcc tgttttgagt ctttgactct ttggatgtgt ttctctctct 45660ctctttgggt cttttttctc ccttttcgtt tctgactatt ttcctatctc taggccccta 45720acaacttctg ctgaagctct gtctcttgaa cactctactt gtcgttgttt gttttcattt 45780ttgagacaag atctcgctct gtcatccaag ctgaagtaca gtggcacaat cacagctcac 45840tgcagcttcc acctctcatg cccaaatgat cctcccacct cagacttgca gtagctggga 45900gtccaggagc ccgccaccaa gcctggctaa tttttgtatt tatatatata tatatatata 45960tatatatata tatatatata tatatatata tatatatata tatatttttt tttttaaaga 46020tgggtttttg ccatgttgcc caggctggtc ttgaactcat gggctcaagc aaccccccca 46080cctcagcctc ccaaagtgct gggattacag gctccaacac actctctctg tgcttcttgc 46140cacctctctt tttgcccact gtcccaacca ctcttctctc atttcctgtg ccttcagcac 46200ttacccccat acagtgagat gtcagacaat gctcagagaa gcaaagcaac tgccccgagg 46260ccacacagcc ctccagaggc cagacttggg tagacccctc tcaggcccta cctcccagtc 46320attggacacc ttcttctgcc ctctcctcct atatgacagt ctccttgttc ctcaatccag 46380aaccctggag tgacctcaga gaacttccag agttagatca cagctgatga gaaggatttg 46440ctgataggca gagggtgcct gggctgctca gcaggggaag ggtccagccc ctgggaggac 46500ctgagtgcca ggcccactct gacacatgct gtctccacct acagatgaca atctgggagt 46560gtgctggcag gaagtggggg ctgacctcgt gtgcagccac cctcggctgg accgtcaggc 46620cacctacaca gagtgctgct gcctgtatgg agaggcctgg ggcatggact gcgccctctg 46680ccctgcgcag gactcaggtg ctggcactgg cctaggctga actcagaggc cttgccccat 46740gggctccaaa tctaggccct cagatcccca gtcgcagaac ccccagactc tatccaaact 46800ctgtccccta gaccaacccc tatgtcgcag cccatcccaa aatcttggtc cccgattcac 46860actccaaaga cttccaagtc tcagccacag acatcccaag gcctgaccca gcagatccca 46920tagtaccaga cccacaggcc cctgaggtct ggtctctcat atgctcagct cctggtctct 46980agaaccacca gacacagcct atgagatgtc ctcccctaaa tcctgggccc ttagacctga 47040aatgccagtt gctcagacct caccatcctg gccccagacc ccctggtcac agccccacag 47100acctccaagt cccattgcct tagacaccct ccaagtccca ttgccttaca caccacatcc 47160gggtgcctaa gaccccaaca cacagcccca gagattccca agtcttggtt tctacaacct 47220ctgagtccct cagtcctcag cccttaggaa cccagttcca aagccccagt cctgggtcct 47280cagacctcca ggtcccagtg cctcagactg tctcccatgc atcctgcccc ctcaggtccc 47340cagcagcaat ccctgggatt ccccagtcct ggtccacaga acacccccat ctaatttctt 47400caggtcccta gtcctagctc ccatgggtcg ctccaattcc agcctctcag accctgattc 47460ttagcaggct tcattaccct tgatctcagc acgtccgaat cccagtctca gccttcagat 47520tctcagcgct ggctccagaa accccggggc cacccaggac cctccccatc cagtcctctg 47580cctcctctcc caaggggggt atgtgagtgg tgggtgtggg ggccagcagg ggctgattgt 47640ttgccttggc tcctgttccc agatgacttc gaggccctgt gcaatgtgct acgccccccc 47700gcatatagcc ccccgcgacc aggtggcttt ggactcccct acgagtacgg cccagactta 47760ggtccacctt accagggcct cccatatggg cctgagttgt acccaccacc tgcgctaccc 47820tacgacccct acccaccgcc acctgggccc ttcgcccgcc gggaggctcc ttatggggca 47880ccccgcttcg acatgccaga ctttgaggac gatggtggcc cctatggcga atctgaggct 47940cctgcgccac ctggcccggg cacccgctgg ccctatcggt cccgggacac ccgccgctcc 48000ttcccagagc ccgaggagcc tcctgaaggt ggaagctatg ctggtgagca ctgccagcgc 48060atgatgagac tgagatgagg ggtgaggtgt gcacggagag aggagggagg gaaacagaag 48120gcgggaggag agacggaaca caggtgcaac tggagagagc cacagaaagg gacagagaag 48180tgtctatagc ccggcaaaga aagagaaggt ggcagaggga aagctggcga gagaatgagg 48240taagcttact ggccccgcag cacccgccac agccctggag cgggatggac agtttacagc 48300gagaaagatg gagccaagga cgcgcaccca ccgttgtggg taaggggtga aggcagggac 48360ctcaagtcat agggtccccg catttcccac aggttccctg gctgagccct acgaggagct 48420ggaggcggag gagtgcggga tcctggacgg ctgcaccaac ggccgctgcg tgcgcgtccc 48480cgaaggcttc acctgccgtt gcttcgacgg ctaccgcctg gacatgaccc gcatggcctg 48540cgttggtgag ggcgggcccg gggccagcat gcgcagggag aggcgaggct tgtccaggga 48600gggtggaagc cctgactagg gggtgctggt cagggacggg aaaggacctc actacagggg 48660acgggccagc gcaaaaggga ggagtaattc ttccacctgg gtggggcttg actgaagaag 48720gcggagtcag ggtgccagca gggcagggct taaccacggg gctggagccg ggccttgaag 48780caggatagag gaatagaata gtgctggtgt gacttgcagt gctaccttgg gcagtctgca 48840ggacctcttt ggagagcctc agtcttccca cctgtaaaat gggaatatta atcaagtctg 48900cctaatttgg atggcagtaa agccaagtga ttaaaatcaa gaacatagcc gggcgcagtg 48960gctcacgcct gtaatcccag cactttggga ggccgaggcg ggcggatcat taggtcagga 49020gtttgagacc agcctggcca atatggtgaa accccgtctc taaaaataca aaattagccg 49080ggtgtggtgg tgcatgcgtg taatcccagc tactcgggag gaacccagga ggcagaggtt 49140gtggtgagcc aagatcgcgc cattgcactc cagcctgggc aataagagca aaactccgtc 49200tcaaaaaaca aacaaaactc gaggaggtca catagacctc agactcagtc cagcaacttg 49260ctgtgtgacg ctggacaggt cactgtccct tacctaattt ttctgatatg aaaaatggct 49320acagtcaaag atcccatttc atagaattgc gaatattatt aacactgatt tacaataaca 49380ttgagagtca tgtgcaaatg gaggcacatg cgtaaaacga

attacagtac ctacctaata 49440ggggtattag aaggacaaag ttaatacttg taatgtgctt aaaacaatgc atgaacattt 49500attgttgttg acaccatcat cagtattttt ttcttctttt ttttttcttt tcttggcgac 49560agagactcac tctgtcgccc aggctggagt gcagtggcct gatctcggct cacagcaacc 49620tcctcctccc aggttcaagc gattctcctg cctcagcctc tcgagtagct gggattacag 49680gcgcccgcca ccatgcctgg ctaatttttg tattcttagt agagacgggg tctcaccatg 49740ttggccaggt tcgtctcgaa ctccggcctc aagtgatcca cccgcctcag cctcccaaag 49800tgctgagatt acaggcatga gccaccgcgc ccggccatta ttattttctt aacaaaatcc 49860tagtgcggta tgggccacca tatccatctt acagaacacg aaactgaagc acagtgaggt 49920taagccacct ggccgggctc acacagttag cagatggcag aggccagatt ggactccaaa 49980ctgctcagca tctgtgctcc tctgttccaa gaacttaagg ggccaaggag gcgagcttct 50040ggggccccag ccttcagcag cgatcgttgt ctcccctccg cagacatcaa cgagtgtgat 50100gaggccgagg ctgcctcccc gctgtgcgtc aacgcgcgtt gcctcaacac ggatggctcc 50160ttccgctgca tctgccgccc gggattcgca cccacgcacc agccgcacca ctgtgcgccc 50220gcacggcccc gggcctgagc cctggcaccc gctggccgcc cacccgcgcc cgccactcgg 50280ggcccctgcc gcgcatcctg cagcccgctt atgcgtatgt gcacggggcc gcccgcctgg 50340acctggagaa gggacctacg gacgcctgga agctgcgacg ccctgcactg ctcccgcctc 50400caccagcgcc tcccactgat gtcgtggtcc cgggcctggc ccaggggccc ctttacatgc 50460cctctccctt ttataaaatt ttccattaaa aaccacctat tttctatctt ttgcctcctc 50520ctgtctattt ctccaagtct accccagttt gtgctttgag tcactaaatg acattccctt 50580cccttctgac ccctagtttc gtctgtctct ctgcctctct tggtctctgt cttccttctc 50640tctctgtctc tgtcgttcta tctcatctct gtctctttct gatttgtttt ctctgcctaa 50700cctctacatc ctgtcttttc atttctgttt ctgcatgcgt ctttctcttt tcccttctct 50760ttgtttggtt ctttcatctc gagagcaatc ttgcctctgg attttttttt tttttttttt 50820tttttttttg agatggagtc tcactctgtc acccaggctg gagtgcactg gcgccatctc 50880catccactgc aacctctgcc tcccggtttc aagcgattct cctgccttag cctcccaagg 50940agccgggatt acaggtgcac actacaaccc aggctaattt ttgtattttt agtagagacg 51000gagtttcgcc atgttggcca ggctggtctc aaactcctgg cttcaggtga tccacccacc 51060ttggcctccc aaagtgctgg gattacaggt gtgagccacc gcacccagct tttatttttt 51120agagatgagg tctccctatg ttgcccagtc tggtctcaaa ttcctgggct caagtgatcc 51180tcccacctcg gcctcccaaa gtgctgagat tatagatgtg agccaccgtg cttggcctag 51240aagtcttaag ctgtcctgga acaagtgggg caagagcagg gagcaggagt ccctggaggg 51300ccaaacccag acctgacgct ccagctagga gttggctgtg gatggagtat ggagcggcag 51360tcctgacagc tggaggcggg aatgagctct gtgtgtgatg gtggagtgcc cagcacggac 51420ctcctccatg tgccctgcct gcttactggc catgttccta gtccagactc ctcctcccta 51480aaaaacaaga acggcctaga tcagcataaa cttagggcag gagtaggggt cgggaatcgt 51540gggtgatcaa cttggcactg ggccaagctg ggaaaaaaaa aaaaaatgta cctcagccag 51600gcgcgatggc tcacacatgt aatcccagcg ctttgggagg cccaggcagg cggatcacga 51660ggtcaagaga tcaagaccat cctggccaac atggtgaaac ctggtctcaa ctaaaaatat 51720aaaaattagc ccgccatggt ggcatgcaac tgtaatccca gctatttagg aggcggagat 51780aggagaatca cttaaaccca ggaggcagag gttgcagtga gccgagatga cgccactgca 51840ctccagtctg gcgacagagc cagactgcat ctcaaaaaca aaaacccaca aaactgtacc 51900tgtcattctt cacccacctg tcaattcttg tgtccccagg gtttcaaact catatgctgc 51960aaagaccaga accggaatgt tagcaggaag cagggaaaat tgaggcacac attaccttct 52020gcctaaggct tggttagact aggaagggga attttcccca ttgttaatac ttttttttgg 52080cctggcgggg tggctcacga ttgtaatccc agcacttcgg gaggccaagg caggatgatc 52140acttgagctc gggagtttga gaccagcctg gcaacatagt gagaccccat ctctacaaaa 52200aagtagctgg gtgcgatggt acatgcctgt agtcccaact acttgggagg ctgaggtggg 52260atgattgctt gagcccagga ggtcgagact gcagtgagct gtgatcgtgc ctctgcattc 52320cagcctgggt gacaaaggca taccttgtct ccaaaaaagt tttttttaat gtatattttt 52380aataactatc tgatattgtt tggctgtgtc cccacccaaa tctcatctca aattgtaatc 52440agaattgtaa tccggggaag gacctggtgg gaggtgattg gatcatgggg acagtttccc 52500ccatgctgtt atcgtgatag tgagtgagtt ctcacaagat ctgatggttt tataaggggc 52560tcttctccct tggctcgctg tctctcctgc cgccttgtga agaaggtgac tgcttcccct 52620ttgccttctg ccatgattgt aagtttctga ggcctcccta gccatgcaga actgtgaatc 52680aagtaaacct ctttccttta taaattaccc agtcttgggt ggtatcttta tggcagagta 52740agaatggacc aatagggccg ggcacggtgg ctcatgcctg caatcccagc actttgggag 52800gctgaaacag gtggatcacc tgaggtctgg agttcaagag cagcctggcc aacatggtga 52860aaccccatct ctactaaaaa tacaaaaatt agcagagcat ggtggtggat gcctgtaata 52920ctacctactc gggaggctga ggcaggagaa tcgcttgaac ccaggagccg gaggttgcag 52980tgagctgaga ttgggccact gcactccagc ctgggtgaca gagcaagact ctgtctcaaa 53040aaaaccaaaa acaaacagaa aaagactaat atagtaccct atggggccta tttggcctat 53100gaggctccag ttttaatcct ctaggcactg ctgaaattgc ataaattgtg gattggaggc 53160tgcttcctga cctgatctcc agcccacccg ctgagtgtca ggaggggtca catgcccagc 53220agcctcctgt gctacatcgg ggaatcatac taagagcgcc taccctgcag gattggtggt 53280ggtggttaaa tgaattgtca tatatgtgct tagaatgtca cctggtacag agcaagggct 53340cagtcattgt tggcataacc ctgggcctcc caggatatgc tgagccctgt ggctgggcag 53400atagtaaggt cttgttcttt tctcttttcc tttccttctt ccttttcttt tctttctttc 53460tttctttctt tttttttttt gacatagggt cttgctctgt tgcccaggtt ggagtgcagt 53520ggtgccacca tggctcactg cagcctcaac ctcccaggct caagtgatcc tcccacctca 53580gcctctcaat tagctggaac tgcaggcatg tgccaccatg ctcagctaat tttttaattt 53640ttattttttg tagagagggg accttactgt gttgcacaag ctgatctcaa actcctgggc 53700taaagtgatt ctcctgcact ttggcctgcc aaagtgctgg gattacatgt atgacccacg 53760gcacctggcc tggctaggtc tttttcttta ccaattctcc ctcccagggt ggaggaggag 53820gccagacccc atccccttca acaggacagt gagaaacacc taacacaagg ccttggtggg 53880gaggagtgtc agacaaggag tggctcaagg ctccacaaag gggtgacagt tgcacaaaac 53940tgtctgtacc aaaaatcatt gaattataca ctacacatgg gtgacttgtg tggtatgtga 54000atcataagtc aataaagccc ttctttaaaa acgccgactc tacaaagcgt ttcagaaagt 54060taccctccag ctgatacagg gaacccgacc caaccactaa ttcctcagtc attcattcaa 54120caaatatttt cctgctttgc aataagtgaa ttcgaggaac acaaacttta acccagcctt 54180ggggggtggt tagggagggc tcctggagga ggagatgttg gagctgagag ttgattactg 54240tagggaaatg agcaagatga aaggggtgga ggtgcctata atcccagcta ctccggaggc 54300tgaggcagga gaatctcttg aacccgggag gcagaggttg cagtgagcca ggattgcacc 54360gctgcactcc agcctgggca acagagtgag actctgtcag aaagaaagag agagagagag 54420aggaaggaag gaaggaaaga aggaaggaaa agaaagaaag aaagaaagaa agaaagaaag 54480aaagaaagaa agaaagaaag aaagagaaag aaagaaagaa agagagagaa aaagaaaaga 54540gaaagaggtg gagaaccatg ttccaggtgg aggggacagc acttccgaag gcctagaagt 54600aagagagcaa gtgtctgtta gatgtctttc ctttggtatc taaggcctgt attggacaac 54660aatggtgaca atcttggtgc ctgagaaatc ccaggccctt gccttcatgg gggacaccga 54720cacatcacca cacatgagag cctgtgctgt atgggggagg cacaggcagg ggtcaggctg 54780cggtggggga agatcagagg gcatgcatgc ccagaggaga cacttgatcc agtctgagag 54840atgatcaggg aaggctttct ggagaaagag acaaagctct gaacagtctc tgtttgggcg 54900tctagatccc tttgagaatc tgtcgaaagc tcattcacag aagaaaaact cacacaaaca 54960aaggttgcag gcaatttcca agtattctca tccttcctcg gaatcttctg tgggtatccc 55020attcccaccc cgcccccaca accaccttgc tgcataaatg tcccaggaat tgcgacaggg 55080ctggccaaca gtgctggaaa actgcaatcg aatttcagca tcctgggagt gggatctttc 55140ttctgagatc tcgcccgccg ccgggcctgg agggtgtgcc ccatggatct aattgttatc 55200ctgcctgcat cccctgcact aacccccaga cctggcgttg gggcttctgg cactggccgg 55260gaccgacgcg ttctcctctg gaatgttcag agggaggtag tccaggcggt caccgcgctc 55320gccagacaag caacgcagcg ccccccgatg gccaccgcgc gccggcgcag cccaagccgg 55380ctgcgccccc tagtggccga tgctcgtaaa gtcttcagcg agccccgagc ttttgctagc 55440cagcccttgg ttttgcaggc tggggtcatc gtcgttgtca tcgttggcat catcatcatc 55500atcatcatca tcatcatcat catcaatagc tagtaggctt ggcgtggtgg cccacacctg 55560taatcctagc actttgggag gccgaggcag gtggatcact tgaggccaga agttcgagac 55620cagcctggcc aacatggtga aaccccgtct ctacaaaaca gtacaaaaaa gcaaccgggt 55680gtggtggtgg gcacctgtaa tcccagctac tcgggaggct gaggcatgag aatagcttga 55740acctggaagg cggaggttac agtgaactga gatcgaacca ctgcactcca gcctgggcaa 55800cagagtgaga ctctgtctca aaaaaaaaaa aaaaaaaaaa gctatgatca tccaggcagt 55860gattcatgcc tgtaaccgca gggctttggg aggccaaggc aggaggatgt catgaggcca 55920tgagttctag actaacctgg gcgacagagc aagagctgtc tctataaaac aaaacaaaat 55980gctatagacc agacgcagta gctcacacct ataatcccag tgctttggga ggccaaggca 56040ggcggatcac ctgaggtcag gagttcgaga ccagcctggc caacatggtg aaaccccatc 56100tctacacttt gaaaaccact actttaactg tctctcccac agggagagct gcctccttca 56160ctctcagctc atttggttca catgttgacc ctactggaag actccagacc tggccagtga 56220gagaatccct tcccttcagc ctttgcaact ggcttaggga caggtgtgtc cctgaagctg 56280gactgatgag cattggctct ggaactactg ctgattgttg aagaaggggc ttcctagaca 56340tactgtgctg aaagggcaca ggcttggaac actgggttct tacatgggag aagagctggc 56400ctgaaaatgc agccaacacg aggggaagca gcgctgggag aggaacagag agactggtgc 56460ctggcgcacg tcatctgcac ctctgtctca cccttctcca gaacatttct ttgcatctta 56520catcaaattt gtcagcaaat tctgtcggct ctagttagaa aaggtgtccc attctgtgtt 56580ggaggaaaag cgatgctgtc tatcaggacg ttaccgggtc agttgacaga actggaatac 56640gaacagtcga ttagaaaaat tcacatacta atattaaatt tactgaagtt gatcactata 56700ttgtggtcat gtaagagaat atccctattc ttttgttttg ctttgttctg tttttgagac 56760ggagtctcgc tctgttgccc aggctggagt gcagtggtgc aatctcagct cctgcaacct 56820cctcctcctg ggttcaagca attctcctgc ctcagcctcc cgagtagctg ggactacagg 56880tgtgtgccac catgcccagc taattttcgt attaatattt ccagtacaga cggggtttca 56940ccatgttggc cagggttctc gaacttacgg cctcaagtga tctgcccacc tttgcttccc 57000aaagtgctgg gaccacaggt gtaagccacg tcgcctggcc agaaatatcc ctattctttt 57060cttttctttt cttttttgag atggagtttt gctcttgttg cccaggctgg agtgcaatgg 57120cgaaatctcg gctcactgaa gcctctgcct ctggggttcg agaaattctc ctgccttagc 57180ctcctgagta gctgggatta caggcaccca ccaccacacc cagctaattt tttgtatttt 57240tagtagagac agagttttgc catgttagcc aggctggtct tgaacttctg acctcaggtg 57300atccgccccc ctcggcctcc caaagtgttg ggattacagg catgagccac cgctcccggc 57360caaatatccc aattcttaag aaatacatag ggcggctgag cacattacct catgcttgta 57420atctcagcac tttgggacac tgaggtggga cgatcccttg agcccaagag ttcaagacca 57480acctgggcaa catggcaaga acccatctct caaaaacttt aaaaatgatc caggtgtggt 57540ggctgcagtg tcaaggctgc agtgagccag gatcatgcca ctgcactcca gcctgggtga 57600cagagtgaga ccctgtctct acggaaaaaa agaaagaaaa gaaaaagaga tacattacag 57660aagtttttgt ttgtttgttt gtttgtttgt ttgagacagt cttgctctgt cgcccaggct 57720ggagtgcaga gtgcagttca gttcactgaa atcctggttc actgcaacct cacctcccgg 57780gttcaagtga ttctcctgcc tcagcctcct gagtagccag gactacaggt gtgtgccacc 57840acacccaggt aatttttgta tttttagtag agacaaggtt tcttcatctt ggctgggctg 57900gtctcgaact tctgacctca gatgattcgc ctgccttggc cttccgaagt tctgagatta 57960taggcatgag ccaccgtgcc cagcccatta tagaagcttt taggggtgat gttgtttgta 58020acttagcctc aaagattttt ttaaaaatca gaaaaagaaa atacataaca gagaagagag 58080caagtgataa aggaaatgag gtagaaatgt taccaatcca tgaacctgag tataaaatac 58140aagagagttc tttgtcctat tatttgtctt gcaacttttt ggtaaatttg aaattatttc 58200caaaggaaaa gttaaaacac tttctaaaat tgagagatct aaaatcttag gccaggcgtg 58260gtggctcaca cctgtaatcc cagcactttg ggaggctgag gcaggtggat cacatgaggt 58320caggagttgg agaccagccc ggccaatatg gtgaaaacct gtctctgcta aaaatacaaa 58380aatcagctgg gcatggtggg aggtgcttgt aatctcagct actcaggcac gagaatcgct 58440tgaacctggg gagcggaggt tgcagtgagc cgagatggcg ccactgcact ccaccctggg 58500taacagagca agactccaac tcaaaaataa tatgaaataa aataaaatct tagacaacac 58560tatcattata agtaggattg gggagatcaa aaacaacatg ctctgtgctc caggtactgt 58620ttggtgtgat gttgaaaata ttagatttta aacttgattt tttctttttt ttttttttga 58680ggcagagtgt tgctctgtcg cccaggctgg agtgcagtgg cgtcatctcg gctcactgta 58740acctccgcct cctaggttca agcgactctt ctgcctcagc ctcctgagta gctgggacta 58800caggtgtgcg ccaccacacc tggctaattt ttgtattttt agtagagacg gggtttcacc 58860atattggcca ggctgatctc gaactcctga cctcatgatc tgccctcctc ggcctcccaa 58920agtgctgaga taacaggcgt gagccactgc gcctagccta gacttgattt tttaaatttc 58980tgtcctccaa tagaaataga cctgattttt aaaaatgtgc atggccaggc acagtaattc 59040atgcctataa tcctaggact ttgggaggcc aatgtgggag gatcacttga gcccaggagt 59100tggagatcaa cctggacaac atagctagac cctgtctcta caaaaataaa aatattaggt 59160gggtgtggtc ttgtacacct gtagtgccag ctacacaggg ggttgaggag ggaggatcca 59220ttgagaccag gagttccagc ctgcaacgag ctaggatctc accactgcac tgcaggctgg 59280gcaacagagc aagaccctgc ctcaaaaaaa aaaaaaaaaa aaaaagcatg ttaaaatttc 59340aaagattgct acaaaaagaa agaaatggtg catagattcc aaactagtag agggaaaaca 59400aagaataaga aaacataaga caaaactaaa caaaaaatgc agccaattca aagaagctta 59460aatgagcatg aaaaaataaa taaacgtaga aaaatgagga cactagaatc acaaagcaaa 59520atggtagaag taaataaaat acatcattaa tcacatacac aaaaaatgta ttcagggcca 59580ggtatggtgg ctcacacctg taatcccagc actttgtgag gctggggcag acggatcact 59640tgaggcaaca agtttgagac tagcctggcc aacatggtga aaccccatct ctaccaaaaa 59700tacaaaaaaa aaaaaaaaaa aaaagaagaa gaagttatcc aggcattgtg gtgcacgcct 59760gtaatcccag ctacttggga ggctgaggta ggagaattgc ttgaatccag gaagtggagg 59820ttgcagtgag ctcagattgc accactgcac tccagcctgg gtgacagagt gagactccct 59880ctcaaaaaca aacaaagaaa aaatgtattc agaggccaaa tacttcttac cacctccata 59940gctgccaccc atatcttacc ctcctcctag ggtttggagt tcctactcct ggccccacaa 60000tctctccccg tcatgcagat agagggactc tgggaataac caagtcaact caactccctc 60060tgctgctcaa aactttcctg tggctccatc tcactcaaag attattttgc tcattttttt 60120tttgtttttt tttgagacag ggtctcactc tgttgcccag gctggagtgc agtggtgcaa 60180gtcatgactc actgcagcct agacttcctc ggctcaagcc atcctccagg cctccagggc 60240taccacaacc cagccaattt tttgatagag acgaggcctc ccttattgcc caagctggtc 60300ttgaacttat gggctcaact tatctaccca cctcggcctc ccaaaatgct gggattccag 60360gcctgagcca ctgtgttccg ccaatctcat tcaaagtaag agccaaagtc ctcactgtgg 60420tccagcagac tctgcaccgt ctgcttcttg ttccctctct gacctcacct cccctccacc 60480ccccacacgc tcctctgcag caacacggat ctccttgttg tttctctaag atccagacat 60540gttcccatcc caccccagga ccttggcact ggctgttccc tctgcctagg ggactctttc 60600cactaggttc agtttctctt tttttttttt tttgagacgg agttttttca ctcttgttgc 60660ccagactgga gtgcagtggc acgatctcgg ctcacagcaa gctcctcctc tcaggttcag 60720gcaattctcc tgcctcagcc tcccgagtag ctgggactac aggcacccgc caccaccccc 60780agctaatttt tgtattatta gtagagacgg ggtttcacca tgtggccagg ctggtctcga 60840actgctgatc tcaagtgatc catctacctc agtctcccaa agtgctggga ttacaggtgt 60900gagccaccgc gcctggcccc cttggctcag tccctcacca ccagcagaag aatggataaa 60960ctgatcccac agtggcctgc aatgtgtgtg tgctgcaatg agaataacct gtaactgcac 61020acgacaacca ggatgaattt ttttcacggt gctgactgaa aaaagccaga tgctaaaaag 61080aacatatttt cagattgcat ttacatgaat tcaaaacagg cacaaccaat ctatgctgtc 61140agaagtgagg gtgataatga ccttggaggg agggcaggtg ataagggagc gccgaggggg 61200cttctggggg gctggagata ttgcttcttg ggctggtggc tggtgacaca ggtgtgttca 61260atcggtgata attcctccag cggttacact tacggtttgt actttcctga atatgggtct 61320acttcaagaa accactgctg aaaacgagga gctgcaccca ccacccagtg tcccctccat 61380ccagtttaag caacaggaca ttctcagccc cccggggtcc ctccctccca atgcaatgtg 61440cttttatgtc ttcaaggggc ctggccacca ccttggttgc ttcccccagc ttgctatgca 61500tgtcacccca cgcatgttcc aggcagctcc acagaggtcc ccagagagaa ggcaggctgt 61560gggtgggagg aagggcaggg gtgggggacg tggcttccca gcggagcccg ggcaggggga 61620ggaaacattt ctgcaacacc ccacaccaag tcctgacttc gggggggctt tgcagggtga 61680attctaagtg cccagggccc catgtgaagg ggtcaactgt gtctcactct gtgtctgtct 61740ctctgtctgt ctctcttcct gtttcctccc tccctcccag tctctctctc ctcaagaaga 61800aaaaaactca caactattta cataacaatt ttatatcaga ctgtaaccca aaaacccaag 61860ttccaacttc gaatttttca ataaactttg aataaatagt agtgctattt ttctttcttt 61920ttttttttag tactgtaatg tttactttta aatttaattt ttactggcag actttacgta 61980tatgaggttc aagaaaagaa aatctccact gtttacattt cttttctgac tattaatatt 62040gttcatttca tttcctgatt attactggca ataattttgt cctatgggga agggaggcgc 62100ttggcaggcc tcgagttatc ctttgagaca tgggggtctg tggtcagatt tagaaagtgc 62160ttgtgggtgg ctgggtggga gtgggtcatg ggagacataa gggcaggctg gagtccaggg 62220aggaggccgg ccgggcaggg acccaggcag cggagatgga cagggccatg gagaatctgg 62280gaggcgcagg ccctggggac tgtggattgg ggaaggagat aattttattt tattatattt 62340ttttgagaca gagtttcagt ctgtctccaa gactgtagtg caatggcacg atctctgctc 62400actgcaacct ctgcctcccg agttcaaggg attttcctgc ctcagcctcc caagtagctg 62460ggattacagg cacgcaccct cacacccagc taatttttaa tatttttggt agagacgggg 62520tttcaccata ttggccaggc tggtctcata ctcctgacct caagcgatcc acctgccccg 62580gcctcccaaa gtgctgggat tacaggcatg agccacgacg tctggcctaa ttttttgtat 62640ttttaggaga gacagggttt tgccatgttg gccaggctag tcttgaactc ctggcctcaa 62700gtgatccgca cacctcaacc tcccaaagtg ctgggattac aggtgtgagc cactacgccc 62760cgccaaggga aggggagaat ttgagtgcta ttgaaggtag aaaacacaga acataggctg 62820ggtgtggtgg ctcatatctc taatcccagc actttgggag gccaaagtgg gaggctggct 62880taatcccagg agttcgagat cagcctgggc aacatagtga gacccctgtc tctacaaaaa 62940attaaaaatt agccaggcat ggtggcaccc acctgtactc ccaaggctac ttaggaggct 63000gaggtgggag gatcgctgga tcccaggaga tctgaggtga gccgtgatca tgccactgca 63060ctccagcctg ggcagcagag taagaccctg tctccaaaaa taaaaaataa tttaaaataa 63120agcgcggaac actgtcaggt tgtctgtggg ggagcagcgg gcaggcgacc aggagggctg 63180gctgctctgt gcagggctag tgcctgggtt gggatgactc ggcctcagag ctgtaaataa 63240agaaggaaga gggccgggcg cggtggttca cgcctgtaat cccagcactt tgggagggcg 63300aggtggacta atcacctgag gtcgggagtt cgagacaagt ctgaccaaca tagagaaatc 63360ccatctctgc taaaaataca aaattagccg ggtgtggtgg cacatgcctg taatcccagc 63420tactcgggag gctgaggcag gagaatcgct tgaacccggg aggcagagat cacagtaagc 63480cgagatcaca acactgcact ctagcctggg cagcaagaac aaaactccat ctcgaaaaaa 63540aaaaaaaaaa agtagaagaa agaaagagct gccacagttg agagcttcct ggatgccttt 63600gttaactctt ggggttttca catacccatc ttacagatgg ggaagctgag gctcagagag 63660aggaaggccc aagtggaaga gcaagcctgg agcccaggtc tcctcctgcc taatcctggg 63720cttttgctgg tggactcccg cccaatcttg aataacttca ggccttaaac aacctcccac 63780gattgctttt cctcccatta gaacaataaa tgcagataca aaaaccaact atgcttgtct 63840acaaagccca agagaatttt tgaagtaata aaactgtcat gaatgcagac tgtggtgatt 63900acatgactta cgaatttttc aaaactcaga atcgagccag atgaaatgat cctgcctgca 63960atcccagcac tttgggaggc tatggcagga ggatcatttg aggccaggag ttcaagacca 64020gcctggccaa catggtgaaa ccccgtctct actaaaaata caaaaattag ctgggtgtgg 64080aggcacatgc ctgtaatccc agctatttca gcagctaagg caagaaaatt gtttgaaccc 64140ggaggctgag gttgcagtga gaaatgatcg tgccactgca ctgtagaccc tgtctcaaaa 64200accaaaacca aaaccaaaaa aagaaaaaaa aacccttaag aatcaggatt atacacgagc 64260acacgcacac tcacccataa attttaccat ttgtagaaaa gaagaagaaa attcaaaacc 64320aaatacaatg aatgtacttt ctctggattc caattcacac caaacaactg taaaaatctg 64380tttttgagac aattggggaa cacaaactgg cttttaggag atattaagga atttcggtta 64440attatgctag acttgataat gccattgtgg ttgggtaatg

cccacatacc atgccttggc 64500tgggcgtggt gactcacacc tgtagtccca gcattttggg aggcccagat gggaggattg 64560cttgagctca agagttcgag accaacctaa gcaacatagt gagacctcat ctctacacaa 64620aattttaaaa aacattagcc gagtgtggtg gggtgcgcct gtaatctcag ctactcagga 64680ggctgaggtg ggaggagtac ttaaacccag gagtttgagg ttgcagtgag ctgagattgt 64740gtcactgcac tccagcctga gcgacagagc aagaccgtca aaaaaataaa gaaagaaaag 64800aaaatgtacc ctattcttct cttcaaggtg ctcattgaag tatttacaaa tgaaacaaca 64860taatacctct cacctgtaat tttttaaaat ttttatttat taatttttta gagatggggt 64920ctcattctgt tgctcaggct ggagtgcagt ggcatgatca cagctcactg taacctcaaa 64980cttctaggct caagtgatcc gcccgcctca gtctcccaaa tagctgagat tacaagcact 65040ggccaccatg ctttgctaat gttttaaaaa ttatttttgt agacacaaga ctatattgcc 65100caggctggtc tcagactcct ggcctcaagt gatcctccca acttggcctc ccaaagtcct 65160ggaattacag gcctgagtca ccgtgcctgg ccaatttttt tttttttttg aggtggagtc 65220tcgctctgtc gcctaggctg gagtgctgtg gcctgatctc ggctcactgc aagctccgcc 65280tcctgggttc acgtcattct cctgcctcag cctcccgagt agctgagact acaggccccc 65340accacgcctg gctaattttt tgtattttta gtagagacgg ggtttcacca tgttagccgg 65400gatggtctcg atctcctgac cttgtgatct gcctgcctcg gcctcccaaa gtgctgggat 65460tacagacgtg agccactgcg tcctgccctg cctggcctat tttttatttt tatgtttttt 65520acagacaggg cctcactatg ctgcccggac tcgtctcaaa ctctgggctc aagcgatcct 65580tctgcctcag cctcctgagt agctgggact acagggtgtg attttttttc aagtattcaa 65640aaaaatgggg aggggaaaga agatgaaatg gcaaaatatt gatggttctt gaacctgggt 65700gatgagtata tgtaagctta ttgtctcttg actttttgtg tctgtttgaa aattttcatg 65760atataagagt ttaaaaactg aaaataaaat ttattgaagg agagtttggg ccgggtgcaa 65820tggctcgcgt ttataatccc agcactttgg gaggccaagg caggtggatc acctgaggtc 65880agaagttcaa gatcagcctg gccgacatga caaaacactg tctctaccaa aaatacaaga 65940atcaggctgg gtgcggtggc tcatgcctgt aatcccagca gcactttggg aggctgaggt 66000gggtggatca caaggtcagg agttcaagac cagcctggcc aagatggtga aaccccgtct 66060ctactaaaaa tacgaaaatt agccaggtgt tgtggtgggc gcctgtaaat tccagcaact 66120tgggaggctg aggcagagaa ttgcttgaac ctgggaggca gaggttgcag cgagccgaga 66180ttgcgccact gcactccaac ctgggggaca gggcgagact ccttctcaaa aaaaaaaaaa 66240agaaaaagaa aaagaaaaat tagccaagcg tggtggcagg cacctgtaat cacagctact 66300cgggagctga ggcatgagaa tcgcttgaac ccgggagacg gaggttgcag tgagccgaga 66360tcgtgccact gcactccagc ctggggtata gagcgaggct ctatctcaaa aaaaaaaaaa 66420aaaaaaaaaa aaaaaaaaaa aggagagttt ggcgttcatc aagcaacatt tggaaactac 66480agagaactag caaggcaaag acgcccctcc catccctaag tcctgtacca ctatggttgt 66540tgacattttg atatatttcc tttcagcctt ttctattctc tgtgagcttt ttaaatgcgt 66600gtgttgtgtg tgtgcacgtg tgtgttttac ataactgtgt gagcaaattg tttatacagc 66660cctgtttttt cccctcttaa aatgtaagct gttcccctgt taaaacatct ttggataaac 66720acaatctcta atgtttgcac tatgtttatt caaaagggca gcattgccag aggttgaagc 66780tgtttccaat ttcctcccat tataaataat cccctcatgg acctccttgt gtgtcccaga 66840ggagggattc ttgggccaaa gggtgcggac cctttggcag agctcatggt caaaaatctc 66900ggcagagttt cagcctgacc cgaagctaag atgacctcat acggttaaag tgagattgga 66960ctgctattta tttcctgaac gtttgattca tgactcaggc ttgtcagggg atcttttttt 67020tttttttctt ctgtatgtgc ttggttgcaa gaaacagaaa tccattcaca ctagctcacg 67080tcaaaagggc aagagaatcg cttgaacgcg ggaggcggag gttgcagtga gccgagatcg 67140cgccactgca ctccagcccg ggcgacagtg cgagactccg tctcaataac aaacaaacaa 67200acaaaaaaag ggcggggggt gttgtatcct tcagcaagta aagctcatat tcagcttgga 67260ctagctgtct gcggagcatg ttgttggggt atatctaggc tatgttgatt gttgaaatac 67320tgaattattt ccgtattggt tggtaaatca ttctgtctca agtcgctcca atgacgtcct 67380ccaccaaggc cactctagct gccctggtcc ctctcccagg acttcccaga cctctccaca 67440atgcaggaag taaagggtca atatcgggca cagaagtgaa ccatgctgct cggtcagtgc 67500ccaaagtatt ggttgtgaaa ttcatttttt cttttctttt tttttttttt ggagacaaat 67560tctcactatg gaactcaagc gatcctcctg ccttggcctc ccaatgtact gggattaagg 67620tgtgagccac tgcacctgga ctgcttgtaa aatatttgat gattcgccta gatgcaagta 67680ccagaacagc tgactcaaat ggcttaaatt gtaaggggaa tctgtggctg gaaaatccac 67740acttgtgctg gcttcagcca aagttgacac aatggctcag ccatgtcacc aaggactttc 67800ttttctttct ttccttcttt ctttcttctt tctttttttc tttcttttct ctctctttct 67860ttctctctct cttttttttt tttttttttg acgtagtctg gttctgttgc ccaggctgga 67920gtgcagtggc acaatcttgg ctcactgcgg caacctccaa ttccccggaa ttcaagtgat 67980tctcctgcct tagcctcccg agtagctggg actataggta tgtgccacca cgcccagcta 68040atttttgtat ttttattttt ttatttatta tttttttaat cattcttggg tgtttctcgc 68100agagggggat ttggcagggt cacaggacaa tagtggaggg aaggtcagca gataaacaag 68160tgaacaaagg tctctggttt tcctaggcag aggaccctgc ggccttccgc agtgtttgtg 68220tccctgggta cttgagatta gggagtggtg atgactctta acgagcatgc tgccttcaag 68280catctgttta acaaagcaca tcttgcaccg cccttaatcc attcaaccct gagtggacac 68340agcacatgtt tcagagagca cagggttggg ggcaaggtca cagatcaaca ggatcccaag 68400gcagaagaat ttttcttagt acagaacaaa atgaaaagtc tcccatgtct acctcttcct 68460acacagacac agcaaccatc cgatttctca atcttttctc cacctttccc cattttctat 68520tccacaaaac tgccattgtc atcatggccc gttctcaatg agctgttgag tacacctccc 68580agacggggtg gtggccgggc agaggggctc ctcacttccc agtaggggcg gccgggcaga 68640ggcgcccctc acctcccgga cggggcggct ggccgggcgg ggggccgacc cccccacctc 68700cctcccggac ggggcggctg gccgggcaga ggggctcctc acttcccagt aggggcggcc 68760gggcagaggc gcccctgacc tcccggacgg ggcggctggc cgggcggggg gccgaccccc 68820ccacctccct cccggacggg gcggctggcc gggcagaggg gctcctcact tcccagtagg 68880ggcggccggg cagaggcgcc cctcacctcc cggacggggc ggctggccgg gtggggggct 68940gaccccccca cctccctccc ggacggggcg gctggccggg cggggggctg acccccccac 69000ctccctcccg gacggggcgg ctggccgggt ggggggctga cccccacctc cctcccggac 69060ggggtggctg ccgggcggag acgctcctca cttcccagac ggggtggctg ccgggcaaag 69120gggctcctca cttctcagac ggtgtggctg ccgggctgag gggctcctca cttctcagac 69180ggggcggttg ccaggcagag ggtctcctca cttctcagac ggggtggccg ggcagagacg 69240ctcctcacat cccagacggg gcggcagggc agaggcgctc cccacatctc agatgatggg 69300cggcctggca gagatgctcc tcacttccta gatgggatgg cggccgggca gagatgctcc 69360tcactttcca gactgggcag ccaggcagag aggctcctca catcccagac gatgggtggc 69420ccggcagaga cgctcctcac ttcccagacg gggtggcggc cgggcagagg ctgcaatctc 69480ggcactttgg ggggccaagg caggcagctg ggaggtggag gttgtagcga gccgagatca 69540cgccactgca ctccagcctg ggcaccattg agcactgagt gaacgcaact ccgtctgcca 69600tcccggcacc tcgggaggcc gaggctggcg gatcactcgc ggttaggagc tggagaccag 69660cccagccaac acagcgaaac cccgtctcca ccaaaaaaat acgaaaacca gtcaggcgtg 69720gcggcgcctg caatcccagg tactcggcag gctgaggcag gagaatcagg cagggaggtt 69780gcagtgagcc gagatggcag cagtacagtc cagctttggc tcagcatcag agggagaccg 69840tggaaagaga gggagaggga aaccgtgggg agagggagag ggagagcgag agcgcatcag 69900agtattttaa cagcagaatt gatcaaacag aagaaagaat tagtgagttt gaagacaggc 69960tatttgaaaa tacacagtca ggccgggccc agtggttcat gcctataatc ccagcatttt 70020gggaggctga ggtgggcgga tcacctgagg tcaggagttc aagaccagcc tggccaacat 70080ggcaaaaccc cgtttctagt acaagtacaa aaattagcca ggaaatggtg gcatgtacct 70140gtagtcccaa ctactcagga ggctgaggca caagaatgac ttgaacccag gaggcagagg 70200ttgcaatgag ccgagtttgt tccattgcac tccagcctgg gtgacagagt gaggctcttt 70260aaaaaaaaaa aaaaaaagtc caggcgcagt ggctcatgcc tgtaatccca gcactttggg 70320aggcggaggc gggcaaatca cctgagatcg ggagttcaag accagcgtga ccaacatgga 70380gaaatcctgt ctctactaaa aatataaaat tagccgggcg tggtggcaaa tgcctgtaat 70440ctcagctact caggaggctg aggcaggaga attgcttgaa cccaggaggc agaggttgtg 70500gtgagccaag atggtgccat tgcactccag cctgggcaac aagagtgaaa ctcttgtctc 70560aaaaaaaaaa aaaaaaaaaa aaaaagatga aagaaagaaa gagaaagaca cagagacaaa 70620aaaagaagag aaagaaaaag aaagaggaag aaagaaagag agaaaagaat aaaaaaaaag 70680aggaagaaag aaaggaaaga aaaaaagaaa agagaaagga gggagggaag gaaggaagaa 70740aggaaggaac gaacaaacac agtcacagga gacaaaagag aaaaagtttt ttgtattttt 70800aatagagacc gggttttacc atgttggcca ggctggtctt gaactcctga cctcaagtga 70860tctgcctgcc ttggcctccc aaagtgctgg gattacaagc gtgagccccc gtgcccggcc 70920agaccccatt tctcccattt ctttttatct ctctgcttta tcttttccag tggaagctcc 70980caagatgact acctccagcc tctggccaca gggaaccttc ttcatatccc acaagcaaag 71040gagagcacct ttggctcagg tttcctgcca aagtaatgag gctaactctg attgggccaa 71100cagagggcac gtgttcatgc aagagccaat cactgtgatc ggagggacag aaggaaaaac 71160cataatggcc agattggctg agccaagtca catgttcctc aaatagtaag gtgagtggct 71220cacactaggg ctgcaggagc cacacctggg ttcaatttcc attccaaaca aatttctgtc 71280ttctctgccc tgtttcccgt cagtaacata gagataatga aggcactcat atggtagagt 71340tcccgtgagg attaaatgag ttagttaatg caaagcactg agaatggtgc ccatatacag 71400aaagcgttca aatgttagct tctgttatcg tcattacatg gccattctca cctcttaagg 71460ctgcttttct ttgcaagctc cttatgctcc acacatttcc ctctttctag ttactattgc 71520ttggtaacaa atcactccaa aatatggtgg cccaaaacaa caacagtcat cctattattt 71580ttcactgtgt ctgtggtcag agttttggga aggacccaac tgggcagttc tgacttggaa 71640tttcatatgg ttgcagtcac ttggcagctg aaactggaac agggaagcag ctgggggtgg 71700atggatctct ctctctctct ctttctctta ctctctcccc actccatgtt gtctcagggc 71760ttctcaatgt ggtctctcca cgcgaactgg tttgggctcc ctcacatcat gacagcctct 71820gggcagttgg acttacatgg cagcttcggc atccagtaca agtgttttat gaaagtagca 71880gccgcgactg ggtgcggttg ctcacgcctg taatcccaac actttgggag cttgaggcag 71940gtggatcacc tgaggtcggg agtccaagac cagcctggaa aacatggtga aatcccgtct 72000ctactaaaaa tacaaaaatt agctgggcat ggtagcacgg gcctgcggtc ccagctactc 72060aggaggctga ggcaggagaa tcgcttgaac ctgggaggcg gaggttgcag tgagccgaga 72120tcacgccact gcactccagc ctgggcgaca gagtgagact ccatcgaaat gaaagaaaga 72180aagagaaaga gagaaagaga gaaagaaaga aggaaggaaa gaaagaaaga gagagaaaga 72240aagaaaggag ggaaggaggg agggaaggag ggaaggaagg aaggaaggaa ggaaagaagg 72300aaaggaaggg gccttatctc ttctgatcta gccttggaat catgcagcat tacttctgcc 72360acatagtctt ggttacaagc aagtcacaaa ctgcctagat gtaaggggag cttacacaaa 72420ttccacttcc caatggaagg ggtatcaaag ttctagagga atatatgggc tgggaaacat 72480tgttgccacc atctttggaa gttacatctg gcttttactg gtactgattt aagacccacc 72540tctatacagc ctgtgcccaa taacatccac ctgggcacag ctccaactcc ctgttctaaa 72600cagaaatagt ttattgagaa atctcaatcc cttgggatca aaaacatgac agtttccatt 72660tgttctgcag tgactgctct ctacctgcta tctattgttt tccaagacta tgatccaaaa 72720tcacagcatc caagactgtg tcttttttat ttatttattg ttttcgagac agggtctcac 72780tctgtcgccc agactgtagt gcagtggcgc aatctccact caccgcaacc tctgcctccc 72840aggctcaaga gattctcctg cctcagcctc ctgcgtagct gggattacag gtgcacacca 72900ctactgcctg gctaattttt gaattttcag tagagacagg gtttcaccat gttggccagg 72960ctggtcttga actcctgacc tcaaatgatc cacccacctt ggcctcacaa agtgctggga 73020ttacaggcat gagccaccac agctggcccc aagactgtgt ctttattatt attattattt 73080cgagacagag tctagctctg tctcctaggc tggagtgcag tggtgcgatc tcagctcact 73140gaaaccttca ccttgccagt tcaagccatt ctcgtgcctc agcctccgga gtagctggga 73200ttacaggcac gcaccactac acccggctaa ttttcgtatt ttcagtaggg acggggtttc 73260cccatattgg ccaggctggt cttgaactcc tgacctcaag tgatccaccc acctcggcct 73320cccaaaggtg gctcacagaa gtgagccacc acgcccggcc tgtctattat ttttattttt 73380aaaaataaat gtattgttaa tttccttttt cctgttggat aaaggctaca gggaaactta 73440atgacaattt tgctagagtc tttaatattt ctctcatttt cattcattta aaaacatagc 73500cttcaggcca ggcacggtgg ctcacaccta taatcccagc actttgggag gccgaggcag 73560gtggatcact tgaggtcagg agttcaagac cagcctggcc aacatggtga aaccccgtct 73620ctactaaaaa tacaaaaatt taaaaattag ccgggcatag tggcatgtgc ctgtagtccc 73680agctactcag gaggctgagg caggagaatc acctgaaccc aggaggtgga ggttgcagtg 73740agctgagatc gcaccactgc actccagcct gagcgacaga gtgagactcg gtctcaaaca 73800aacaaataca caaaaaaacc cacaaagttc atggggaggg aaaggtgtag cctctcttga 73860gaactttcct ctctcatttt ccccccaaac aggatgatgc ttcctttctc ttctctatcc 73920ttttctggac agccttgggt cctctcagta acttatttgg gtaagtggct ggttataatg 73980gcagtgacct cgaacttagg ctctggggta gttggccact tttgtcctca gttttgggca 74040gtagtagcaa ttctggaagt tctgggaaaa atccaatttg acatcatagt acgaacctga 74100aggaaaggtc ttgatcccaa agagctctcg gcagctcatg gctgtgactg tcatccaggg 74160cctgggcctg gggaaatgtt tggggatctg tgggatcctt tagggactgt cacagtgact 74220cgggaaatgt tgctataggc aactgttctg gaactttttg gtcttaggac tcttttacat 74280tcttaatagt atcaaggacc ccaaacagct tttatttgtg tgggttataa cttttttttt 74340tttttgagat ggagtttcat tctagtcgcc caggctggag tgcaatagtg tgatcttggc 74400tcactgcaac ctctgcccca caggttcaag caatcctccc acctcagcct cccgagtagc 74460tgagactaca ggtgtgcgcc atcacgcctg gctaattttt ttgtattttt attagagaca 74520gggtttcacc gtgtcggcca ggctggtctc caactcctga cttcaggtca tccatccgcc 74580tcggcctttc aaagtgctgg gattacaggc atgagccact gcgcccggcc tgtgtgggtt 74640atagctattg atatttacca tattagaact taaaactggc catttaaaca aattttttat 74700tattgattga tttttgagac agggtctcac cctgttgccc agagtggagt gcagtggcat 74760gatcacagct cactgcagcc tcgaactcct ggcctcaagt gatcctctcg cttcagcttt 74820ctgagtggtt gggactacag gtgtgcacca ccacacccaa ctaatttatt gatttttttg 74880tatacacagt cttgctgtgt tgcctaggct aaaactgaca atattaaaat ccagccatcc 74940acaagcacac actggcagag caattatgtc atcacatgtc atggagccat tgtatgctca 75000taagtgaatg agattgaaat acgcaaaaaa agtcctggaa ttattatgaa agtaattttg 75060gccgagcgcg gtggctcacg cctgtaatcc cagcactttg ggaggccgag gcgggcggat 75120cacgaggtca ggagatcaag accatcctgg ctaacatggt gaaaccccgt ctctactaaa 75180attacaaaaa aaaattagcc gggggtggtg gcgggcgcct gtagtcccag ctactccgga 75240ggctgaggca ggagaatcgc ggagcttgca gtgagccgag attgcgccat tgcactccag 75300cttgggcgac agagcaagac tccatctcaa aaaaaaaaaa aaaaaagaaa gtaattttaa 75360ctttgtggac aaagtctcag ggacctccag gaaaccctgg accaaacttt gaaacttgct 75420ctaaaagcat ttgtaagcct gggatggtta ggtatgttca acgtgcagcc atgtaggaga 75480tagtgcatgt caaaagggcc cctttggatg ggttaatatc actttggttc agttatctgt 75540ggcctggaag gggtcccttg tgtacaaaca aagctgggga gtaggaggga agaatttttt 75600tttttttttg agacagagtc ttgctctcgt cccccaggct ggtgtgcagg ggtgtgatct 75660tggctcaccg caacctctgc ctcccaggtt caagcaattc tcctgcctta gcctccctag 75720tagctgggat tacaggcacc tgccaccaca cttggctacg ttttgtattt ttagtagaga 75780cggggttttg ccatgttggc caggctggtc aaccctgacc tcaggtgatc caccctcctt 75840ggcctcccaa agcgcaggga tttacaggcg tgagccactg cgcctggccc aggagggagg 75900aatcttaacc ataatgctca tcttgtacta tctactggaa accctaaaaa tacagagacc 75960ctggagccac tttctgggtt ctgctcccct tcattgcttt ctagctgtgt gactttgggc 76020caagttcctt aaccactctg tggctcagtt tctcttctgg aaaatggaga caataatagt 76080atctgcctct cagcgttgtt ataagagtta ccttggcaca cagtgttatg tgggtgttta 76140cgctgagtat tactgttatt acagtaatca ttcaaatcca agaagccatc aaaggtaaga 76200tgcattgttt tttattttat tttattttat tttttatttt tattttgaga cagagtcctg 76260ctctgttgcc caggtgggag tgcagtggtg cgatctcagc tcactacgac ctccacctcc 76320caggttcaaa caattctcct gcttcagcct cctgagtagc tgggattaca ggtgtgccct 76380accacgccta agttttgtat ttttagtaga gatggggttt caccatgttg gccaggctgg 76440tctcaaactc ctgacctcaa gtgattcacc cgcctcagcc tcccaaaatg ctgggattac 76500aagggtgagc caccacaccc agccaagatg cattgtcact tcaaatcccc aggggagaaa 76560aaacagctgc cagttaaact atgacacata atcatttata agacacatcc tgatttccaa 76620gtcattgaaa aggggtgggg aggataaata agtcaattaa aaatggtttt attcggcctg 76680gcgtggtggc ttacgtctgt aatgccagca ctttgggagg ctgaggtggg tggatcacga 76740ggtcaggaag ttcgagacca gcctggccaa cgtggtgaaa ccccgcctct actaaaaata 76800caaaaaatta gccatgccta gtggcacagg cctgtaatcc cagctactcg ggaggctgag 76860gcaagagaat ctcttgaacc cagaaggcag agattgcagt gagccaagat cgtgccattg 76920cactccagcc tgggtgacag agcaagactc catctcgaga aaaaaaaaaa aaaagatggt 76980tttattctgg aataggagag tatttaagga aagaaaataa aaaataaagg aaaaaaagaa 77040attttaaaat taaaaaaaat gatttcatgt gtacagaaga atttagcaac aaggatgtcc 77100accacagcac ttgtcataat ggcaaacctg ctgaaacccc aaccattatg gattaactgc 77160acaagttaag agagagccac aaaatattgt gactgaaggg gttttcaaag attgttccaa 77220aaccctgggg atcctcaaaa gtgaatcaat ttctctcttt cataatcttt ttcatcttca 77280ctctcctatg agtgcataaa gcaaaaaata ataagcaggt gacttctaaa aagaaaaaac 77340ctctggaaac tatgcctcaa ccccattcta gagcctgctg ggccactgct cagaaaagga 77400aatgtgtgcc ccaggctgac ccactcttaa gacaacccat tctccacatg cctctgcctt 77460cagttacaca gctgtaccca gagaggggtc ttgtctttac tcagctgtcc atccaccctc 77520cctgtgttgc aatgaataca tccctggtat cttctgtgcc tggccccagc ccaccccctc 77580ctcagagctc cagccacaca ttccagtgcc ttcgagactc acctgctttg aaaggtagat 77640ccttacattc aattttcttg ttgaaatact tcatgtggtt tcttttttct tgacaagcct 77700ctgaccaaca cttggtggtc attcttaaac cgttgatttt tccccttcac acctattccc 77760ctccacgatc acaatcttcc cagtctcaaa aatgtctcta cctgggacct caagccagaa 77820acccaggcaa tatggaggca cttcctctcc tcattccaca tatgccactc atggacaatt 77880cctgctttcc tctaaggcag atgcttacca cacccctacc cccacccttc tatttagaaa 77940atttctaaac atgcaaaaga attgcaagaa aagtagaaga tataataata tactgtggat 78000atggattcac taggtttttg cagttttttg tttgtttttg ttttgagacg gagtcttgct 78060ctgtcaccca ggctggagtg caatggtgcg atctcagtgc aagctctgcc tcccaggttc 78120aagcaattct ccctgcttca accttccaag tagctgggat tacaggcacc caccaccatg 78180cccagctaat ttttgtattt ttcagtggag atagggtttt gttacgttgg ccagctggtc 78240ttgacctcct gacctcaggt gatccgcctg ccttggcctc ccaaagtgct ggattacagg 78300cgtgaaccgt cacacctggc cttttgtgtt tttgtttttg ttttggtttg tgtgtgtgtg 78360tttgtttgtt tgtttttgag atggggtttc actctgttgc ccaggctgga gtgcagtggt 78420gtgatcacag ctcactacag cctcaacctg ctaggctcaa gcgatcctcc cttctaagcc 78480tcttgagtag ctgagactgc aggtgcccac caccacaccc agctaatttt tgtatttttt 78540gtagagacgg gttttcacca tgttgcccag gctgttctca aactcctggg ctcaagtgat 78600tccccccacc ttggcctccc aaagtgcttg gattacaaac gtgagccact gtgctgggcc 78660tatttctttg tgttttaaga ggcagggtct ttctctgttg cccaggtgga gtacgatgat 78720tcgatcatag ctcactgcag cctcaaactc ctaggcacgg gagaccctcc tgcatcagcc 78780tcccgagtag cccagactac aggtgtgtgc cactatacct agctaatgaa aagaattttt 78840ttgtagacat gagttcttgc tatgttgtct aggctggtct ggaacctcca gcctcaggcg 78900atccccttgc ttcagtcttc caaagcagtg gggttacagg cgtgaaccac ctggcctggt 78960ctcgctcttt ctctttcgac atctacattg atctgtagct atctacgtac tatagatatc 79020taaaagttat gtaaatgtct acttaagctt ataggtatga gctactgtat gctatctaag 79080cttataggta tgagctacaa attgctattg tgttatgagg ggaattcaaa aagttgatgg 79140agaatggaat taagagataa aaattttaaa aaaatcttta tttctcacca taaactccat 79200caaggtcaaa gtcaagacac ttttgtaaac cattatacca gccatttagt ctatccctaa 79260ataactgagg gtcccaggaa tttaatcatg tcagtgcagc ctttttacat tttctctttc 79320tttttttttt tgatggaatc tcactctgtt gctcaggctg gagtgcagtg gtatgatctc 79380ggctcactgc aacctctgcc tcccgggttc aagccattct cctgcctcag cctcctgagt 79440agctgggact acaggcatgt accaccacat ctggctaatt tttttttttt tagtagagac 79500gaggttttgc caagttggcc gggctggtct caaactccta

acttcaggtg atctgcccgc 79560ctcggcctcc caaagtgcta gcattacagt tgtgagccac tgtgccaggc cttttttttt 79620tgttcttgtt gcccaggctg gagtgcagtg gcatgatctc ggctcactgc aacctccacc 79680tcctgggttc aagtgattct cctgcctcag cctcccgact agctgggatt acagtcatga 79740gccaccacac ctggctaatt tttgtatttt tttttttagt agagacaggg ttttgccatg 79800ttggtcaggc tggtcttgaa ctcccaacct caggtgatcc accctccttg gcctcccaaa 79860atgctaagat tacaggcgtg agccactccg cccagcccag tctttttaca ttcttaactg 79920aagaaaaatg ggtgcccttc aaagatttta agattaggaa acaaaaagtc agaaggagcc 79980aaattgggac tgccaagtgg atgcctaata atttcccatc aaaacttgta aaattgctcg 80040tttgatgagg agaatgagca gaagcgtaga catgctggag aagaactctc tggtgaagct 80100tcccaggctt atttctacta aagcttcggc taactttctc aaaacactct cataataagc 80160agatcttatt attctttgac cctacagaaa gtcaaccagc aaaatgcctt gagcatcccc 80220aaaaactgtt gctatgacct ttgctcttga ccagtgtgct tctgccttga ctggatcact 80280tccccgctct tggcaatcat tctctgatta cgatttgtct ttaggattgc acccgtgaaa 80340ccatgtatca tttcccgtta caatccttca aggaaatgca ttaggatctc gatctcactt 80400gtttagcatg tccatggaaa gctctgctct tctctgcagc tgatctgggt gcgaccgttc 80460tggcacccat cgagtggaaa gtttgtttag ctttaatttc agtcagaatt gtgtaagctg 80520aggccgggtg aggtggctca agcctgtaat cccagcagtt cgggagaatg aggcaggagg 80580atcacttgtg tccaggagtt caagaccagc ctgggaaacc taatgagacc cccatctcta 80640caaaaaatac gaaaatttag tgtcaggcct ctgagcccaa gctaagccat catatcgcct 80700gtgacctgca cgtatacatc caggtggcct gaagcaactg aagagccaca aaagaagtga 80760aaatagcctt aactgatgac attccaccat tgtgatttgt ttctgcccca ccctaatgat 80820caatgtactt tgtaatctcc cccaccctta agaagtttct ttgtaattct tcccatcctt 80880gagaatgaac tttgtgagat ccgccccctg cccgcaaaac attgctccaa actccaccgc 80940ctatcccaaa acctataaga attaatcata atcccaccac cctttgctga ctctcttttt 81000ggactcagcc tgcctgcacc caggtgaaat aaacagcctt gttgctcaca caaagcctgt 81060ttggtggtct cttcacaggg acgcgtgtga cacttagctg aacgtgctgg cacgcacctg 81120tagttccaac tacttcggag gctgaggtgg aaggatcgct tgagcccagg aggttgaggc 81180tgcagtgagc cacaatctca ccactgtact cagcctgggc gacagtatga gaaccctgtc 81240tcaaaaaaaa aaaaaaaaaa aaagaaaaaa gaattgtgta agctgtacca attgagatgt 81300ctatggtgtt ggctattgtt tctgctgtta actgtaagtc ctctttaatt aaggcataaa 81360caaatttaat ttttttctgc aaaaattgat gtggatggta tgccacggtg ggcttcatct 81420tcagcatgac ccaggctgga gtgcagtggc gcaatcacgg ctcactgcaa cctctacctc 81480ccagactcaa gtgatcctcc cacctcagcc tcctgagtag ctggaactac aagtgtgcac 81540caccacaccc agctaattta tgtatttttt gtacggatgg ggtttcacca tgttacccag 81600gctggtctcg aattcctgag ctccaatgat ccgctggcct cagcctccca aagtattggg 81660attacaggcg tgaaccacca cgcccgaact tgtcccttct taaaacgagt tatccatttg 81720taaatggctg atttctctgg ggcactgtca agtttttgga aaacatcaat gatttcatca 81780ttcttccacc caagcttcac catcaatttg atgcttgttc ttgcttcaat tttagaattc 81840gtgttgctct gataggggct cttttcaatc tgatgtttta ttttagtgtc tcaaactagg 81900tcctgttcag acaagttata acaagttagt atgaatttat tttggtgcaa aaaaaaaaaa 81960ttgaactcca tgcatagttt tttcataata cacattttcc atgaattttt ggaagaccct 82020tctttttctc tctttttttt tttttttttt ttttctgtag agatggtctt gttctgtcac 82080ccaggctgga gtgcagtggc acaatcatgg ctcactgcag cctcgacctc ctgggctcaa 82140gcaatcctcc cacctcagct tcctgttact gggactatag gtgtgcacca ccacaccttg 82200ataattaaaa aaaaaaattt ttttgtagag atcggggtgg gggggggggt ctcactatat 82260tttccaggct ggtcttgaac tcctggcctc aagtgaccct ccccaatcag cctcccaaag 82320tgctgggatt acaggcacaa gccacagtgc ctggccaata aatgtttttt gaatgaatga 82380agaaattagt gcatggacat attttcccat cagctattac aataaccaga ctctgagttc 82440cctgaaggca gggcctgtga gtttcattgt gtaccctcag ccctcaatag ctgataaaaa 82500taaatattca gaaaatgctt gtaaaatgaa gaagagaata tgtatgggac agaaagtaga 82560ccagtggttg cctggggctg ggacagggaa tagggagcga ctgcaaatgg gcagaaggga 82620tcttttcaga gtgatggaaa tgttcttgaa ttggctgtga tggctgcaga actgtaaaat 82680cacccaaaat cagtaaatca cttataatag gtgaatttta tgacaggtag attatacctc 82740agtaaagctg ttaaaacaaa accagtgttg agggaggaaa taaatgttac cttggtaata 82800ctgaggactc agtagttatc aagacagctc tcttccctgc cctcatgagg ttttctgtgc 82860agggcgggga cgccgaccca ttatagacag tgacagccta gagccatcac ggcgggatgg 82920tggggagggg acaggcagag gggtgggagg ccaggatggg ggaagcccgg gcagagaggt 82980tgggctggaa tggggggcac aggcagaggg gtcggggcgg ggactggtga ggtgcaggca 83040gagggcaaag gggtcgaggt ccagatggga gatgtacagg cagacggatc cgggccaggg 83100cggggaggta caggcccagt tgaggagcat aaggaaccat aggagcccaa aggaggcgcc 83160cgaccagtca gggaggactt cccagagggg tgaatggctg agccagggcc tgaagtataa 83220tgttcatgaa tgcgacagca attttttttt ttttgagacc gagtctccct ctatcactgg 83280agtgcagtgg ctcgatttcg gctcactaca acctccacct accgggttca agcgattctc 83340ctgcctcagc ctcccgggta gctgggacta caggcgcccg cccccacgtc cggctaatgt 83400ttgcattttt agtcgagacg gggtttcgcc attttggcca ggctggtctt gaacccctga 83460cctcaggtaa tgcacctgcc tcggcctccc aaagtgctgg gattacaggc gtgagccacc 83520gcgcccagca caattttaat ttttcttaaa cacttttcct gccttagcaa agtcttggag 83580gggcggccgc ccaggcgccg cgagcgcaag accacgaggg ggcgctgctt caccacgcta 83640gaggagcgct cccggcaacc acgtggcccc acaggtgcgg gaggtcggcg agcgcgcctg 83700gagggtggac ggggtaggtt acggccaggc agcccggggt ggcgcgtggc cctgcgcagg 83760gcagtggaag cagcgggccc cagggagcat gagacgccgc gctccgtggg gcggtcccag 83820cgctgtgcag cgaggggcca gggctgtccc cggtcctgcg cggccggctc ccggagaaac 83880tgtggcctcc tgggggtgga gctttaaaaa acaaaacaaa acaaaacaaa atcacccaac 83940aggaagcggg gtgggggcgc ccggctctgt cacccgtgga atgcatcaaa atagcctgcg 84000cggccggggg cggttccggg aaagggggcg gccgcgaggg gcggggctgc aacggagggc 84060ggagcttccc aaagaacggg agagaggagt gcagaaccgg ccccaggggg acgtcctcct 84120gttcccccaa aatgacctcg ataggcgttt gtgtgggatg gggttcctgg gtagggcggg 84180gctttccagt gcgatgtccc tggtctattc ttagcgggct gaaacctgga gaagtgggag 84240tgggcggttg atccgggttc cagggcctct ttggagcgaa aagctccgtg gagagccaga 84300gtctccatcc tgggcgtggg agggaagatg ggaaatgggc caagaggagc ctgtgggagg 84360tcctccccgg gacggccccc ttccatctgc atccgcggga accgttgtgg gggcagctct 84420gagaaaggct gctctgggcg caaggaaggg tggttgaacg aagagatcag tcagggacgg 84480ggtgggggtg ccttgactgt gtcccagatt tgctgcgtgc ttctgacctc agttccccat 84540ccttccagtt gctcaaatcc tctctgtccc agtcctaggc cgtttctgcc cctctcactt 84600cctagtggtt tgcagagggg aaacactgag gctgcctctt ctgtgcctgg ccctgtgttg 84660gcacggggaa gtgactgaga cgccccagac ccccttctcc ctcacagtcc agtgaggcag 84720acagacctgc caccagatag tgacagccca gaatgagtca ttgagaggac gggggaggca 84780caggcagatg ggtcagggct gggatagggg aggagagggg cctgtaggat ccaaggggag 84840agtgggtgct gctgactcag tctggggggg ttgaagagcc gtctgaactt agaccaaaaa 84900ggtaggatgg ggccgggcgc ctgttatccc agcactttgg gaggcagaga caagaggatc 84960gcttgaggcc aggagttcca gaccagattg gacaacatag cgagaccccc atctctacaa 85020aataatttaa aaatcagttg ggcatagtgg tgtacgccta tagtcccagc tactcaggag 85080gctgaggtgg gaagattggt tgagcccagg aattcaaggc tgcaatgagc tatgattgcc 85140ccactgcagt ccagcccggg tgacagcgtg agacccctgc ctccaaaata ataatagcaa 85200aaatactggg ctgggcgcgg cggctcacac ctgtaatccc aacactttgg gaagccgagg 85260tgggcaaatc gctgaggtca ggagttccag accagcctgg ccaacatggt gaaacccagt 85320ctctactaaa aatacaaaaa ttagctaggt gtggtggcaa ggcatctgta gttccagcta 85380cttgggaggc tgaggcagga gaatcgcttg agcccaggag gtggaggctg caatgagatc 85440acaccactgc actccagcct gggcgacaga gtgagactct gtctcaaaaa ataaataaat 85500cctaatgaaa ggataggatg gggctcaggg ccttggaaga gggtcacctt ctaacaaaag 85560gtatttgaac ggagtcctaa agaatgagta gcattcttct gggaagtgct gtgtcaccat 85620gaaggaaagg gtgttctagg cagaaagaat gacaaatgca aaagcttgga ggtgagagtg 85680tggcttatct ctggcagggt cctctgctcc ctgcctggga cattccccca acgtcatacc 85740ccgacagagc tgtcttaggt ctcctagtcc tggagtccac aagcaggtta atgggatgta 85800atggaaacgc tatagagggc agacccctag gcttgttccc tcacagcctg atgctttttt 85860gtttttgaga cagagtctcg ctctgttgcc caggctggag tgcagtggcg tgatcttggc 85920tcactgcaac cttggcctcc caggttcaag cgattgtcct gcctcagctt cccaagtagc 85980tgagattaca ggcacccacc accacgcctg gctaagtttt gtatttttag tagagacgga 86040gtttcaccat gttggccagg ctagtctcga actcccaacc tcaggtaatc cacttgcctc 86100ggcttcccaa agtgctggga ttaaaggcat gagccaccac gcccagcctt ttgttttgtc 86160tgctttttta gacagggtct cacgctgtca ccctcacagg ctggagtgca gtgactgcat 86220cacggaccac tgcagcctgg acctcccagg ctcaagcaat cctcccacct caacctctcc 86280agcagctggg actacaggcg tatgccacca cgcccaccta attttaaaat tattttgtag 86340agacagggtc tcattatgtt gcccaggctg gcctcgaact cctgggctca agcgatcctc 86400ccaccttggc ctcccgaagt gctgggctta caggtgagag ccacctcagt gcccggcctc 86460agcctgatgg tttcacgact gcctttgact ttggcccaca ctaatcaaat gtatcaccgt 86520gggccactga ctcaacttcc ccatctatcc agtgggaata gaatattgga ctgcacaaaa 86580tcaaccacct cattttaaag agctataacg aaacaaaatt tatatgttat atatttttaa 86640aaatacatct tatagattaa aggactcaag aaacaatagc aagactgtaa aacgttgcca 86700catcaggtga cactttggcc agagttatgg aaaatgctga caaaacaaga atttgccagc 86760atgggcaaag atatactgtt accaacccaa cttgttaaaa tattaatatt gagctaatta 86820gaagtagttt tttttttttt gttttttttt tttgagacag agtctcattc tgttgcccag 86880gcaggagtgc aatggtgtga cctcaggtca ctgcaacctc tgctgcctgg gttcaagcga 86940ttcttgtgcc tcagcctcct ggaattacag gcgcctgcca ccacgcccgg ctaatttttg 87000aatttttggt agagactggg tttctccatg gcggccaggc tggtctcgaa ctcctgacct 87060taagtgatct gcctgcctcg acctcccaaa gtgctgggat tacaggcgtg agccactgtg 87120cccagccagc agttcataat atttgttttt tattccttga ttctaactct gtaaggaata 87180gaaatggggt gattaatttt ggctccttta atacccgcct ggcaggtgct gagtcagtgg 87240tacctgttac cacgctatga ctcagaggtt atcactcagg gacatccttc tgactctgtt 87300tcagtccatg actcaggagg aaaggttcta gggcctcacc agcgccctac acacaccctc 87360gtttcccgag gggcaccatt atattcttcc tttattggct gtccttgtat aatacaaatc 87420ttcaagttta gatacaaaaa aaatctggaa ataaaagata gaaaagtacc cgccaggcac 87480cccttcccct tcttcccgga cccctcccca gcgggcaccg acatgaggta actgcgcatc 87540ttctcctcct cctccctccc cgcctcctgg gcccccaact tggccctagc ccccatgaga 87600ccttggccca aggaagacat gggccccaaa gttggagggt gatggaggtg agtacagcat 87660tggcagtgaa cgcagcgtgt gggcagaggg cagcccttag cttgtgctgt gcatgggggg 87720aggagacgac cagatttggg gtgggcactg gtgtggggcc caggagagcc cctaagcaag 87780tgtcccccct ccatcctgtc caacactgga aggtgggggt caacagaaac tgggaaatgg 87840agtgtgaacc aagggcattc agtgggattg tggccaaccc ctgtgtctgg ggttggggaa 87900gggggcattg ccagcctaag tccggcagtg aaatggttcc cttagccagg ctgggtccgt 87960ccctgaattc catcctgttg caacctgggc gtcacaatgt tggttctgta gtggttgtcg 88020gggtggttga gggagggggg tgttgagagg gtgttgaggg gcgcagcccc agggagcagg 88080gttaggggag aggttgtgcc tccaccccca ggcgtggggc acctggagat gatggagtgg 88140gtggggcggc tcgggctaca gttcaatctc gaatgtcttt tgcaggtcgc cagaaaaggg 88200gttggagggt ttctctacag tggctttgcc ttctaatgcc gcccactggg cctcaaaggg 88260gtccaactct ggagctgggg caggcgctgg ctcagggggc cagggggccc cattggggcg 88320agggcgggcc tggctcccag gggcactggg tatggcaggg ggcgggaagg ccccagcttt 88380cccaagcaga gtggcaggct gaggctggag ctgggcggct gagcagaagg cgtttgccac 88440catctgtgag ggtgtgatgc ccaccacggg cacccggggc atcggtgggt agcccaagcc 88500cgggtaggcg ggcacaaaag ggggctgcat gtgtgggggt ggcaggaaca cggccacttg 88560ggcaggtgca gcgtcaaagg gccccacggg ggcggggaaa ggctgcaggg caggaggcat 88620ggtgggcact ggggccactg aggctgcttg ctgctgttgc tgctgctgct gctgctgctg 88680ttgctgttgc tgctgctgct gctgctgggc cttggccacc tgtgacacct cctccagcca 88740tcgctcagcc tctgaaggtg tccgcttgtg cccaggctgg aaggcagctg cagggggcac 88800ggagggctca ccccaggcag aagtccctgg agagaggaga gggacaggtg agggaggggg 88860caacggcttc agcagaagaa ccccaggctg ggaactggca tggtgtgggg atcagagcac 88920ggactctgga gccagaccgc ctgcctctga atcccagctc tgcacctccc gagcttgctg 88980acttcaggcg agtgacttca ccattctgga ccacgtaatg gttctggagt gctaagaaca 89040tacaattctg agcttctaag gccctatgat gagaaagtct aagtaggact gacatcctcc 89100tagccccact acccttctga ctggtcagtg ccaagcctag gattcactat tttgttttgt 89160ttgttgtctg ttcgttttga gagtctcact ctgttgccca gggatgccct atctgggctc 89220actgcaacct ctgcctccca ggttcaagca attctcgtgc ctcagtctcc tgagtagctg 89280ggattacagg cgcgcaccat tacgcccggc tgattttttg tatttttagt agaggcgagg 89340tttcaacatg ttgcccaggc tggactcgaa ctcctacctc aagtaatccc cctgcctcgg 89400cttcccaaag tactaggatt acaggcatga gccaccacac ccagctggta ttcactattt 89460tgaatatcac ccttgatttt ctaatacctt cagaatgtat tgttttagga gttaagattc 89520taagattgca tggatctttc tccacatgta taatagtatc ctaacatagt aaggtttgac 89580agtttagggt tgggctttct aagattctcg agttctacat ttacagtgtt tgagattcta 89640aggtgcacct gtggttctag gataagccca tggctctaag atgatacatg gttctcaagg 89700attccatggt tctgaaacga tctctgggct ctaaggtgat cccaagattc tagcatgagc 89760acatgcctct gaggtgaccc cgtggctcta caatgatccc gtatctctaa gataattcat 89820ggttctaaag tgatcacttg attctcaggt aatcccacgg ctctaagatg atccttggtt 89880ctaggatgat cctctggttc taagatgatc tgtgtttcta aggtgatcct atggctctaa 89940gatgatccat agttctagga tgatcccatg gttctaaggg gatcccgtgg ctctaaaatg 90000atcaagggct ctgagatgat ccatggctct aaggtgatca catgattctc agataattcc 90060atggctctaa gatgatccat ggttctagga taatcccctg gctctaagat gatccctggg 90120tctaaggtga tcacatgatt cttaggtaat cccatggctc taagatgaac cacggatcta 90180ggatgatccc ctggctctaa gatgatccat ggctctaaga tgatcacacg attctcagat 90240aatcccatgg ttctaggctg atcccctggc tctaagatga tccctgcttt taaggtgatt 90300gcatgattct caggtaatcc cgtggctcta agatgatcca tggatctagg atgatcccct 90360ggctctaaga tgatccatgg ttctaaagta atcgcatgat tctcaggtaa tcccatggct 90420ctaagatgat ccatggttgt aggatgatcc cctggctctg aggtgatcca tggttctaag 90480cctgtaggat cccaagaccc ctggagtgtc tgggtagccc tggatagagg aggggataca 90540ggagggacat gcagggtgtc tgcccagcag aaagcctggc tttacctgtt gtggcaggtg 90600gtggccctgg tgctggcgct ccagcactgg caaaagatga actgatctgt gtgcacagag 90660cgttgatgct gtcactgtcg ccggcaccag gaggctccat ctcaggcact gggaagcagg 90720gcaggacaga ggtcagcaaa caggcccaga ccctgccgca gccccgccct ctaccccccg 90780ccctcggtgg ccctctcttc tgacctggat cctttcccac tgtagtaact aagtggccat 90840gaccgccaaa taactgtgca tatgtgtgtg tcacatctga gcggcagaac gactgagtta 90900gtgtgtgaca tttgacggct gacagtaaca gggaccccaa accaaggacc tcaagatttg 90960tgtgtggcca caaaccagaa gagttgtcta aaacacttag caacatatat tagtttaaaa 91020atatgcccaa ccacgtgcat ggcaaggaca tgggcccagt ctgaatgggc tgtggcatgg 91080ccgctcactg gctggggatc atttgtccag ctttgggcag agaagtgggg tcctgtccac 91140cccacccagg ctgatctatg gcaaacatca tgagagcaga gatacacctg tgccagcaag 91200gcaggagaca ctgagcaggc atggcggccc cgtgagggct tgtgatgagc aaaggtacca 91260tccaaataaa caattaagga ctcccatgtg tggtgtgtga cacatgtctg tgatgtttta 91320gccaatggct gtctccaagg gaccatgtag atgctccagt gaacatcaga actggccgta 91380ggagtctgca ggtgtgctgc gggggcgccc gggtgggaca gccaatgtcg acaatgattg 91440tgcatgttcg tccaaacagg aatgcagctt ctgagagtgt gactggggtc cgggtgtgtg 91500gcgtcctgat gcgtgactcc caggtgtgag tgcatctgcc gtgtgatgta tgagtgtgtt 91560tgcaggtgtg catggatctg cacatgtggc tttggagttt gcataaatct gggtgtgtgg 91620tctgtgaagg tgtgtaaatc tgagtgtgtt tcttttttaa aaatatttat ttatttattt 91680ttgacacagg gtctcgctct gttgcccagg ctggagtgta gtggcacaat cttagttcac 91740tgcaacctcc gcctcccagg ctcaagcaat cttcctgagt agctgggact acaggtgcat 91800gccactgcac ctggttaaca ataaaggtta atttttaaaa tttttttgtg gagatgagat 91860cttgctgtgg tgcccaggct ggtctcaaac tcctgagctc aagtgatcct cctgcctcag 91920cctcccaaag tgctgggatt acaggtgtga gccaccacgt ctggccatgt gtgacttctg 91980actctgtgat tttggagtgt gtgtgacttg agagtatacc tgactgtgag tttgtgactt 92040ctgagcatgt gtgacatgtg tgtggggggg tgcaatgtct atgtgagtat gtgaaatttc 92100tgtgtggcaa gtcacatcca aataagcgtg cagctggcca caggagtgtg aggcttccaa 92160ataaagcctg gagctcctgc cacctctcag gagcacgtgt gacagcctgg ggagtgtgcc 92220tgatgtcagg ctgcgttaag gacagcaaat gtgagggtgt gtgatggccc aggaatgctg 92280caggcatgga gggagcgtgc gtcactctca acaagggttg gcatctgctc accggttacc 92340ttttggagca gcccagcctc ctggatacag ctcaacaccc tcccacatca atccccgagg 92400acataacggg taggcgatgc agatttggca tccaggagca agagagtggg ccagaccaca 92460tgggttcact ggctgctggt ggggaagaca gcccttctgc ctgcctccct caggcaaaaa 92520ctcagtagcg tgccacctct atcttccttc cctatggcag agattgctct taattttttt 92580ttttttgaga caggttctca ctctgttgcc caggctggag tgaagtggcg caatcttagc 92640tcactgcagc tgggctgaag caattctcct tcctcagcct cctgagtagc tgagactaca 92700ggcatgcgcc accacaccag gctagttttt gtattttttt gtagagacag ggtttagcca 92760agtgatctgc ctcaagggat ccttgagccc ctcttgggct caagtgatct gcctgccttg 92820gcctcccaaa gtgctgagac cacaggcatg agccactgca cttggctaga catcactttt 92880agatcatgat gtacaccacc tgtctccttt ccctggccca tggcagacat tagtaatcaa 92940acacaatgct tttttccccc acggagctct ttgctcacct tacccgtcac ctgtccagac 93000ctcatggctc ccctggccaa gtgctagaag aaacagatcc ttgtaactcc atcttccctc 93060caagtaaaac aggaccttta tatctcctct ctcttaccac cagccatggc agacaatgcc 93120aatcaattat gatgtgctgc tccttttcgt gatgggtact gcctctgctc aactctgtgc 93180ctacaacaaa tgttcctgat ccatcactat gcccctgacc cctgggatct ctgagctcac 93240tggtgccctg catgtcatgt ttctactgac caaattctgg gagtctcccc tttgggtaaa 93300aacataacac tcttgctact ctttcttctc ccttgcccat gacacacact gcatggagat 93360catgactgct aaccgatcat gatgtgtgcc atctttctcg tttcccttaa ccacagcaga 93420cattgctaat tgatcatgac ttgtgatgcc ttttttgcca tcccttgatg ctccctgccc 93480taggcagaca tttctaatcc atcacaatcc tcctttcctc agagcctgag gaatacctgt 93540atccttcacc tagccagatc tcataggtga atgcttggag ggagggagca ttaacctgta 93600gtgcttcagt ctactcctga gcaaaaacag gccaatggtg ttgcttctct tctttccctg 93660gcccatggca aacttcctta tccatgcccg acttctttgt ccatagccga ctttgctaac 93720taatcatgat gtgtgtcatc tttctccttt tccttaacca caccagacat tgctaactga 93780tcataacttg tgatgccttt ctactatccc ttactcagag cagacacggc ttatcaatcc 93840tgatttgtgc tatctctttc ctctcccttg cccactgcta atcgatcatg acatgttccc 93900actctctctc ctttgcccat ggcagacagt gcaaatcaat cacagtgtga accatctcgc 93960ctccatccct tgcccacatc agatagtgcc aattgattcc aacgccgttt cccactgggc 94020ccagggctca cctgtgccct tcacctggaa gtcagtgcgg cgctgcagcg tggatggcag 94080ctcattcagc cgtaggctca gctgccgttt gaaaggcgag ttcttctggc tgagtgctgg 94140gaacccacgg aaggagccct ggcgaaccag ctgctccagg ggtgcatggc gccgggggat 94200ggcggccgca gtggtgcctg cagccacagg ggtgcctgcc tcacccttct caccagggga 94260tgtggtggct ggtgtcgggg acacgtgccc aggctgggca gggccaggag ccacagtggg 94320ggcagctgct gcctctgctg gagacatggg ggagatggat ggttagatat ctcaccatgg 94380catgcaaggc ctctcccacc tggttctctt gatcattctc caaggctgcc ttccttgccc 94440agtgagtcct gcccttaaga caagctagtc aaagccctga gatatccctc acccccaccc 94500aagtcatgat ccccttcccc aggaggctct tggaaaaccg tcccccaggc tcaccctctg 94560tgtctctcca gcttcctgcc cctttctgtc ttgccctgct

gctctcacca ttcttccctc 94620taagaccctc tatctccctt tttgatcact taacaaacac tgatttggtg ctggaacaac 94680gtatcaggca ttgttccaga tgcttttcaa gtattcactc attcaatcca cacgactacc 94740catggggttg atatgattct cattttacag atgtggaaac tgagacccag caaaggccca 94800gtgtgatgtg cccaagtcct actgctagga aggggcaggc tgactctgga ccccatgctc 94860caaatgactg cccgccctgt ctccctctga cctgtctctc catatcatgt tgtctttctc 94920tgtcactgtc tgttcccctc tgtctcccac ctcccagcct tcttcccacc tcaagtagct 94980cctcccttcc tccagtcatt ctagacatgg cttggatgct tcatcctctg agaagctttc 95040cagattgttc caggctctca gcctggctcc ctccactctg agactgttct ctgtactctg 95100ggaggaaacc tgacctcccc actcagcagg agaggcaggc tcttcaaggg cagggctgcc 95160ctcacccctg ccaaaccaca aacacacatc taccctccta ccagggcctc cccgagctgc 95220agcctgaatg ccatggagat taaactcagg cccagagaga ccctcccata aggatgtcgc 95280ccagtgctgc ttctcccatc gtgacacaat ggggcaccca tgcaggcctg gcccaaggca 95340gtggaaacag cccaggacag gttggaacca ggaaacctcc tctgcctcca ctcactgtgt 95400gacctcagga agtcccctcc cctctctggg ctccagtttg ccaactagaa acctgggata 95460aacatctcag tgctacctcc caagcctctg agagggtcag tttaggtagt gaatgttaaa 95520tgttttggaa tccaacaaaa gcatgcctgg acacagtggt tcacgcctgt aatcccagca 95580ctttgagagg ccaaggtggg gggatcagtt gaagccagga gttcaagacc agccttgcca 95640acatggtgaa acaccatctc tactaaaaat acaaaaaaag attagctggg tgtggtggca 95700cacgcctggg attccagcta ctctggaggc tgaggcagga gaatcgcttg aacccgggag 95760gcagaggttg cagtgagccg agatcgcacc attgcactcc agcctgggca acagagcaag 95820actctgtctc aaaaaaaaaa aaaaaaaaaa aaaaaaaact tagctggacg tggtggcggg 95880cacctgtaat cccagctact caggaggctg aggcacataa atgtcttgaa accaggaggc 95940agaggttgca gtgagctgag atggcactac tgcattccag cctgggtgac ggagagagac 96000tctgtctcaa aaaaaagatg ttcttttttt tccccttaca atccaggatc taattcagga 96060tcacatctcg catctattaa tacctgttaa acctcattag tctcccttaa tcaggatcag 96120ttcccaatgg taaattcttt gtaaattcta agtagtgttt tcccaaagaa cttaaattca 96180cagtaaaata aataaataaa ttaattaatt aataaataaa ttaattatat ggtgactcag 96240gacatacata caattatatt ttaaacacac acacacacac acacacacac acacacacac 96300acagagtttt agaacttaca aagtatttaa ccatttacct agaaagttag ttttaccaag 96360tatgtttcaa actttcttga tggcaatcca gagttaagag atatctttta tatggtagcc 96420tcttacacac gcgtgcacac acacacacac tctctctctc aaataaaagt atcattaaat 96480tatatttaac ccttatgcca ttcaatatac tctgatattt tctatgattc tctatttcat 96540tgtttttaaa ttaatttttt tttttttgag acagggtctc actctgtctg tcacccaggt 96600tggagtgtgg tggtgcaatc gcagctctct gcagcctcta cctcctgggc ccaggtgatc 96660ctcctgcctc agcctcctga ggagctggga ccacaggttg caccaccacg cctggctaat 96720tttttaatga tttgtagaga cagggtttcc ctatgttgcc caggttgatt tcattttttt 96780aaatgtcagc cacatgggct gggcccagtt gtccacacct ataataccag tgctttggga 96840ggctgaggtg ggaggatcgt ttgaggccag gagtttgaga ccagcctggg aaacacagca 96900agatcccagt tctacaaaat ataaaaataa aattagccag atgctgtggc ttgtgcctat 96960attcccagct acatggaggc tgaggcagga ggattacttg agcccagcag tttgaggctg 97020cagggagctg tgatcgcacc actgcactcc agcctgggca acagaattag acctcaactc 97080agacaacaaa acaaaacaaa aaatgccagc cacagtacag caaattggct tcccaggtct 97140taatacacag gttgaaaagc cctgagaagg ccaggcgcgg tggctcacct gaggtcagga 97200gttgaggcca acatggtgaa accccatctc tactaaaaat acaaaaatta gccatgcctg 97260taatcctaac tactcgggag gctgaggcag aattgcttga acccgggagg tggaggttgc 97320agtgagccta gatcacacca ttgcactcca gcctggttga cagagcgaga ctccgtctca 97380aaaaaaaaaa aaaacaaaca aaaaaagaaa agcctcgaaa agccccgaat tggtggatag 97440taaaccactt ggtgcgccct tagaatattg cccagagaac tctttccatg gaagttgctt 97500tatttattta tttatttttt gagacagagt ctcactctat tgcccaggct ggagtgcagt 97560ggcgtgatct cggctcactg caacctctgc ctccagggtt ccagcgatcc tcctgcctca 97620gcctcccaag tagttgggat tacaggcgta ggccaccatg cccagttaat ttttgtattt 97680tagtagagac gaggttttac catgtcgcgc aggctggtct caaacttctg acctcaagcg 97740atccgcccat ctcggcctct caaagtgctg ggattacagg tgtgaaccat ggcgcttggc 97800ctgaagcatc ccctactttg taaactgttg agtctctgca cctctgcagc tccctgcccc 97860ctgatactgg gtaccctgtg cccactctgt gctctgctgg cgcttggggc aacacccacc 97920tttcttcttg tccggggcct ctcgctcagc aggccgccca cccccagaca ggcggaagga 97980gccctcgcgg gcgaagctgg tgcggctggc atcgaaggcg gccgtgaccc cacattcctt 98040ctcccgtcgc tgttttcgct ccaggcaggc ggcaaaagca cagcccacag cgtggctcag 98100cctctcgccc tatggggaga ggatgggcgg gggggttaga ggcgctgggc agtgcggaca 98160ggggccaggg gcactgggtt atagccgcta ggtactgggt tgccccggat gagtctctgc 98220acttctctgg gcctcagtgc tcatctgcac cacaaggaag ggctggaaat gacagctcca 98280agtgagagaa gccagaaacc aatgagcctg ttgtgtggct ccacttactg gaaattccag 98340aagaggcaaa actaatctat ggttctatgg tgaaaaaaag tcagaacagg ccaggagtgg 98400tggctctcgc ctgtaatcct agcactttgg gaggctgagg cgggaggttc ccttgagccc 98460aggaggtcaa ggctgcaagc agctatgatg gggcaactgc actccagctt gggtgacaga 98520gtgagattct gtctaaaaaa aagtcagaat agtggtagtt tcctatgggg tggggaatga 98580ctggaaagtg tatgagggga tgaccgggtg gtggcaatgt tctagatatt gataggggtt 98640tcgttacatg ggtgtatgca gttgtcgaaa ttcgttgact gtacaccaaa ggcttgtgca 98700ttgctataga ctaaacgtgt gtgtctctct cagttctaac gctgaagccc tcatccacaa 98760tgtgctggta tttggaggtg ggcctttgag agacaataaa agttatgtta gatcatgagg 98820tggggtcctc atgatggaat taatgccctt atttatttat tttttttctg ggacagggtc 98880ttactctgat gctatgctgg agtgcagcgg catgacctca gctcactgca acctccacct 98940cccggcttca agcgattctc ctgcctcagc ctctcaagta gctgggatta taggcatgcg 99000ccaccacacc tggttaattt gtgtattttt agtagagatg ggatttcatg atgttggtga 99060ggctggactc gaactcctga cctcgagtga tctgcccacc tgggcctccc aaagtgttgg 99120ggttacaggc gtgagccacc atgcccggcc gggattaatg cccttaaaaa ggaaaaagag 99180acaagagatc tcccctccac cttgagaggt gaagatacag aaagcaggca tccatctgca 99240aaccaggaaa agagccctca ccaagaaatg agccatttga caccctgacc tcaggtatcc 99300agcctctaga actgcggcaa acaaatgttt gtcatttaag ccacacagtc tacactatct 99360ggttatagca gcctgaacta agacaatcat atctttcgct ttgaagaaaa aaaaaatctg 99420gaaacaaata cgaattctac ttaatggtgt gcatgctgaa gtagtccaat gcctacaaat 99480ttgacataca aaaagaatca gacggtgtga ctgcagtcgc tcacacctgt aatcccagga 99540ggccgaggca ggcaaatcac ttgaggccag gagttcgaga ccagcctggc caacatggtg 99600aaaccccatc tctactaaaa atacaaaaat ctgccaggtg tggtggcgtg cacctgtaat 99660cccagctact agggaggctg tggcaggaga atcacttgaa ggttggaggc ggaggtttca 99720gtgagccaag atcgtgccac tgtactccag cctggggcaa cagagcgaga ctccgtctca 99780aaaaaaggaa tgaaccactg atacaagcag ctcacgcctg taatccgagc actttgggag 99840gccaaggtga ctggatcgct tgagtccagg agttcgagac cagcctgggc aacatggcga 99900aatcccatct ctacaaaaaa ttagccaggc atggtggcgt gtgcctgtag tcctagctac 99960tcaggaagct gaggtgggag aatcgcttga acccaggttg cagtgaggcg agattgcacc 100020actgcacacc agccttgatg acagagagag acgctgtgtc attaaataaa ttaattaaaa 100080acattgccgg gcagggtggc tcacacctat aatcccagca ctttgggagg cagaggcagg 100140cggatcacct gaggtcggga gttcaagacc aacctgacct gcatggagaa accccatctc 100200tactaaaaat ataaaattag ccagctgtga tggtgcatgt ctgtaatccc agctacttgg 100260gagactgaga caggagaatt gcttgaaccc gggaggcaga ggttgcagtg agctgagatt 100320gctccattgc actccagcct gggtaacaag agcgaaactc tgtttcaaaa acaaacaaaa 100380acacaacatt acactaagta aagaagccag acacatatta tatgattcca ttaaatgaaa 100440tatccagaat aggtaaatcc acagagagac aaagcagatt agtggttgcc agggggctgg 100500ggtagtgggg agacggggtg aattgatgaa tggagatggg gtctccttta gcggtgatga 100560aaatgtttca ggactgctaa agtcaatggt taaacaacac tgaaaatgta ttaaatgcca 100620ttgaattgta cacttttaaa tgattaattt tatgtgaatt tcacctcaag aaaaaaaaaa 100680agttgaactt ggggaattct actgcttaat ggttaaaact tccttcagaa gtaggaagga 100740attcatccaa catcacattc tttacccaca ggagatggtc ctgctctttt ctggctttca 100800ttctcatccc caaatagttt tttttttttg ttttcttgag acagagtctc gctctgtcac 100860ccaggctgga gtgcagtggt gcagtcttgg ctcactgcaa cctccgtctc cagggttcat 100920gtgattctcc ccacatgtga ttctcctacc tcagcctctg gagtagctgg gatcacaggc 100980gcctgccacc atgcctgtct actttttttg tatttttagt agagatgggg ttttaccagg 101040ttggccaggc tggtctcaaa ttcctgacct caggtgatct gcctgccttg gcctcccaaa 101100gtgttgggat tacaggcgtg agccaccacg cctggccaat actctttttt ttttgagatg 101160gagtctcact ctgtctccca ggctggagtg cagtggtgca attttggctc actgcaacct 101220ccacctcccg ggctcaagtg attctcctgc ctcagcctcc caagtagctg ggactacagg 101280tgtgcaccac cacacctagc taattttttg tatttcagta gagatggggt tttaccatgt 101340tgtccagggt ggtcttgaac tcctgagctc aggcaatccc cccgccccag catcccaaag 101400tgctgggatt acaggtgtga gccactgcac ccggccctca cgtgaatact ctaaattggg 101460aaccgtgagt atactttctt ctccagatga ggaaactggg cacacagagg ttagtgatgt 101520gcctgaatgc aggaagcttg taggggtggg gctgggatgc cagggcatgg gagggaagag 101580ttggccagct gtggcaatac tcacggagtc cttcagtgcc agaaaacagt ggcagatcca 101640gcggcgggta gtcccgtcac gacagatata ggagaaagcc ttgtccaggt tgcggtcagg 101700agcacaaaag gagacctttt cgatggtctg gtcgaccaga agatcctagg aggggccggg 101760gaggccagga gaagagtgtg aactctcttt caagtgttca ctcaacattc tctctgtgtc 101820tgctgaaatc cagtcctgaa cagggtgggg acccagcagt cactgagaca ccctgtgcct 101880tgcctgcaga gggctcccag gtcagcggga agatcagacc catcacgaga tgggcagccc 101940agagtcatag ccaggatgtg atgaaggagg cccaggcaga ggggtcaggg ccaggaccat 102000ggaggcacag gcagaggggt cagggccagc atggcagaag ccagcttggg gtcagtcagg 102060caaggcttcc tggagcaggt actaactaag aaaaaaagtc aaggaacagt attttgggct 102120gagggaactg ccttgcaaag gtggtgatct tgttctgtta ttaacccaac tctcagcatg 102180tcctgggcac ctcctagggc agtctctggg ctgggggcag cagattcaag gtgagcaaac 102240agatacctag attgtggcct catagtgctt ccttctgact gggcagggtg acaataaaca 102300cttaatggct aacattcatt gatctgagca gttacgatgt actagacccc atttaaatat 102360atatatatat ttttttccca gaaggagtct tgctctgtca cccaggctag agtgcagtgg 102420catgatcttg gcttactgaa acctctgcct cctgggttca agtgattctc ctacctaagc 102480ctcccaagta gctgggatta caggcacgca ccaccacgtc tggctaattt ttgtattttt 102540agtagaggtg gggtttcacc atcttggcca ggctagtctc gaactcgtga cctcaggtga 102600tccaactgcc ctggcctccc aaagtgctgg gattacaggc gtgagccacc gtgcccagcc 102660cacatttaaa tttttttaaa aattattttg tatagatgga gccttgctat gtttcacagg 102720ctgatcttga actcctggct tcaaggggcc ctcccagcca ggcaccattt caaataactt 102780gcatatgctt tctcacttaa tggtagggtc tattataatc cctgtttttc tgcgatggag 102840tttagctctt gttgcccagg ctggagtgca atggcatgat ctccgctcac cgcaacctcc 102900aagtctcggg ttcaagagat tctcctgcct cagcctccca agtagctagg attacaggta 102960cacaccacca tgtccagcta atttttgtat ttttagtgag atgaggtttc accatattgc 103020caggctggtc tcgaactcct gacctcaggt aatctaccct ccttggcctc ccaaagtact 103080gggattacag gcgtgagcca ccactcccgg cctataatct gcatttttca gatgacacaa 103140ctgagactca gagaggttaa atctcatgcc cagggtccct aagctgggat cggagctgag 103200gcagctgctc cagtctctct cacccacagc ctatgccagt tcccaaataa tcacagcatt 103260tattcctgag ttatgacgac agagggagca cacggcatcg tctagaaggt ccctgaggga 103320gggatgtgca gaggaggcgg gaaggtgtcc tccgccctga ttccagcagg gtgagcagac 103380aggccccctg gcgtccaccc ccacaggcct cctaccttgg ttttgtcgtc caccactcgg 103440agcccatcgg ctgacaccca caggacagac ttcacggact ttcggcccat ctggagggag 103500gcaaggggac aaaggagccg ggtcagggtg cctctccctg tctgaccttg ccccctccct 103560catggcagcc ccctcactca ccgccttcag cttcttcacc gcatcttcac acacgtgcat 103620tccccgggac tcctctacct ccacgtgacc caggtacttg ggttggaggg aatggggggg 103680gggacatgaa acagcacagt aatcactcat tctcagtgtc cactgagcat ctgccatgca 103740gtagacaata ttttaagcac atgatgtgta tgcaatcatt tattctgcat ctcaactcta 103800caaggtggag accccattcc tggtctagac atgcagatgg ggaaactgaa gcacagcacg 103860tagtagtgat tccagtctag ctatacccct gggccctaac ccggcaccgt ggtcctcccg 103920agagctagta tttgcatctc tgtgcgtgag gactggccac aggccatgca aagctgcttt 103980gcctacccta aagcagctag aaagagcctg ggccagtccc cacaatgact gaagggagtt 104040agggtacctg agccccagct ccctcatctg caggtgggat gactgttgcc tcgagtttcc 104100caggggaaag ctcagttgca cactgctgca gttttaataa cacacccttt actggctgcc 104160ttactttcct cactcccaac accatttcct gcacctccca aatgaagccg tcacattcaa 104220agtctgcttc cagggaaggg aacgtaaggt ggtggagggg ctgtgaccat ggtcagtcat 104280cacccagcca ggaaggggct gagctccaca gtccacgccg tgaatcctgc tctccccctc 104340acaggaatgt aaaagcgtag ggtatggcta aaccagaacg tccttatcgg tagagcgctt 104400tgcaaatgct acaccacatg acggcttcca ggtaatagtt tgctggtaca aaaaaatgtg 104460ttctggtttt ttgtttgttt tcaagattgg gtatcactct gttgcctagg ctggagtgca 104520atggcacaat taaggctcac tgcagcctcg accttcctgg actcgagtga gcctcccacc 104580tcagccttgt gagtagctgg gactacaggt gcgtgccact gtgcctattt tttgtagaga 104640cagggtctcc ctgtgtttgc ccaggctggt cttgaactcc ttgactcaag caatcctccc 104700accacagcct cccagtgtgc tggaattaca ggtgttagcc accactacgc ttcaagtttt 104760tttttttttt tttttgaaac agagtctgct ctgtcgccca ggctggagtg caatggcgct 104820atctcggctc actgcaatct ccgcctcccg ggttcaagcg attctcctgt ctcagcctcc 104880ccagtagctg ggactacagg cgcccgccac cacgcgaggc taatttgttg tatttctagt 104940agagccgggg tttcaccgtg atagccagga ctgccggcct cacgcttttt aacaccaact 105000tcaaacgact tgggctggtg tcccagccag gccgcgcacc cgcacagcac agcacagcgg 105060cccccgtccc cctcgccccg ccgcaccctg ccgcgcccac tcaccctgac cgggaagctg 105120cacgtgccct tccgcaccgc gtcctcgtct gcctgccact ggtgcgggcg cgacgcctcg 105180ggcacgtagg ctggcttcct ccgccgcagg ctctgccgta acttgttcat ggtgcccgcc 105240ccgtctggtg acacaggaca gtgatgtggg tcaagggtgg gggtcagaag gtatggagct 105300caacggggag ggaccagtgc tcagggagca tggggtcaga taacaagata actggaagcg 105360gggttacagg gtcagttggc agcgcacatg ggatcagcag ctcaagtcag gggacagtga 105420ggaaaggagc caacagaagc caggggagtg cgaaagttgg gcactgggga ttcagaacca 105480tggggctaag gggctggagg tctggggtgg ggggtatggg gcacaggctt cagggcattg 105540gagggcttct tgtccatgtg gtggatgctt cctcattccc agggccgtga ggacacaaag 105600ggtgggaaat cagacgtagg agggcatggg ggctagaggg catagaagtc aggggccgca 105660cggtcagggg ttttaggggt atgagagtca ggcagtgggg tgatcagagg gcagcagagg 105720agttgggaat tgcatgggtc aggggtgcag gagtcaggtg catggggtat gggggatggt 105780ggcttgtctc tggaactctg agacacagcc attctgtgac aactgtgtct agtccccagg 105840caaggcttct ggggccttgc actgatgact gtcagaggca gggctgtggg tgtgtggagt 105900gggtgtggag gtggccagcc actaggacag tcttcactga tcagccatcc tgacagtccc 105960aggactggga gcaccaacag cagaggggga tgtgtgtgtg tgtgtgtgtg taagcaagtg 106020tgcaatggta tgttctggaa cgctgtctat gaggggctct atatctgagc aggcaagtaa 106080tgtctgtgag tgtgtttctg aaggctgtct ggaagaacgc atgtctgaga atggtgtagg 106140atagtgtgca tctgtgaatg ctgtccgtga gggatgcatc caaaagtgtg gttgttgtct 106200gtgagtctga ggccctgaag gttgttgctg aagggcatcg atgtctgaga gtggttgtga 106260gtgtgtgtct gctgtctata tccgagagtg ccgttgttgt ctatgagaac ttgtggctca 106320gtgcctgttg cctgtgaggg tgtgtctgtg tttgagatga ggctgtcgtc tttcaaaggg 106380tgtgtccatg gctgttatcc atgtagctat gtctctgtgt gaaggtgtgg ctattgtctg 106440tgatgacatt gcctcggaga gtgcatctga gggatctaca agactgtctg tgtccaagag 106500tgcagctgtt ggcggtgagc ctgtgtgact gtggctgttg ccttagagtg tgggtgtgtg 106560ggtattgcac agagggtgta tctgtgtgca gtggtgcatc cgttagggtg tgtgggaaca 106620tgaggttgtc tttgagagtg ttttcatgag ggttatttgt aagggtgtga ctgttgcctg 106680agagagtgct gggtgttctt tgtgagactg tgtgcatgtt tgtacacaac cgtagctccc 106740tgtgagagcc tgggcccgcg ggtgctgtct gtgaaagtgt ggctgtcgtc tgtagaaatg 106800tgggtctgtg tgtgttgtca gactgtgcaa gagtgtgtct cttttttttt tttttgagac 106860gaaattttgc tcttgttgcg aatgaaggct ggagtgcaat ggcatgatct cagctcacag 106920caacctctgc ctcccaggtt caagcgattc tcctgcctca gcctcccaag tagctgggat 106980tacaggcatg tgccaccacc cctggctaat tttgtatttt tagtacagac agagtttctc 107040catgttggtc aggctggtct cgaactcctg acctcctgac ctcaggtgat cctcccgcct 107100cagcctccca aagtgctggg attataggca ttgagccacc acgcccggcc aagagtgtgt 107160ctcttgagag tgtgtatctc agagtctgta tccagcgagc gtctgtggtc acctgtgaat 107220ctgggtgttg tctaggaatg tgtgtgtgtg tatatatgtg tgtacattag tgtgatgaac 107280atctacttca gcatgtgttc aagtgtgtca ctgcattagc aagtgtgtgt gatctgaaag 107340agatctgtgt gtgtgtgtgt gtctctaacc gtatatctac agatgtgagt gtttgtgact 107400ctgcacttga ggctgtaagg gtgtcagggt gtgggtctgt gcatgagtgg ggctctgaca 107460gtcgctgagg aagatgcctg agggtgtcca ctcatgagtg tgattaagcc tgtgtgaccg 107520cagggacagc tcctctggtc gtgttaggca agaccacata cccattcagc cctgccctgt 107580cccaggctgg tcgctcacct ggctccgtcc tgcaggtttc tgggggcccc ggggccccac 107640agggggctgg gggcaggtgc cgctcaggcc tccggggtcc gccctgcccg agtaggggag 107700gagaaggtga gaagtttgtc tgggttgggg ctcagtctga tacttcaccc cgactttgga 107760cttcggccag ccccctccat cttgggctcc ctgatgagag tcctagttgt cctagcaact 107820gttaccaggg agatcagcca cctggttcca agggcccagg aaggagtagg tatgtttggg 107880gggcatatgt tggggatgtg ctggcctcag gagagcctca ctgcccaagg ggatgctgtg 107940agagtggcct tgccctccag atgcatgtgc agggctacac acatacgcag ccaactcata 108000tctacaggtg tccctagcat ctggccacag ctttacacac ttggttacac atagacgcaa 108060tcacagctac acacctcaga tcgcagatac acagaaacag tcccaaaccc agaaagctgc 108120cactgtaaac atctggccgc atattcatgt tcggacacac acagtctcta ctacagacat 108180ttgtccacat acatgcagca tgtcctggcc cactcagttc ccaccgcaga cacctggtca 108240caccacccac tgaaatttgg tcacttccac attctcagcc acatacaaag aacggggccc 108300agacaaccca ctagagccgc acatgcgtgg ccacacccag tgacagctat gtttcctcag 108360gcacccgccc aagatactga cgtcacaggc ccacccagat agaatcacac ccagagttca 108420cccatttgct gacccagtcc cacacgacac aatcgcagct atatacactt gttacacgta 108480tctccactgc tgcacactga catctggtca cagatgcaca cggacagaca cacatttggt 108540cccacggaga ccacatgcag cctcaaccag accagtcaca ccaacacact gtttttggcc 108600acacactgtc acgtggtcac acatactcag tcataggtgc tcaaatctgg tcacagcatc 108660agtcacacag tctattgtga cagccacact catagggaca gtcctctata cacaaccaca 108720tacagaggta ctgatggcca cagcatgcaa ccacccacaa acaactgtcc ccaaggatgg 108780cctccctcaa gacacagcca tggtggtcct ataggcatgg ccacagcatc aatgtccatg 108840tgacccagcc acctatcatg gtcataatcc cgtcacccag tgtccataca cagctgtacc 108900atgtcactcc aatgcagcga aacatatagc ctttcttcat gcaggcacac aagtcacaca 108960gacaagtatg tggccatata gaatcacagc cccgtgtgga caggtgcaca aagtcacaag 109020ccccacctac acacatatct cacacataga gacataagca cacagtttta gtttcccatg 109080tcacaagtac acagtccagt gtatgcacat aaatgcagtg accaggatgt ggcatttata 109140gctgggttta cacagaagac acaggtcctg acggagccat gtgcacagtc aggggccaat 109200ctcatcacca aatcacacat tctaacacag gtagtccagc acatacacac agagacaaaa 109260acaggcacac agctacagac cccacactct cacagatgat gacatagaca cagacatcta 109320tagtcaccca gggtcagaca tgcaggtcaa acacaataat atggaagcca taatcatata 109380cacaccccta caaacataat ttcctggcac cagcacggag acacatccac agctttagtc 109440acacacaaat aatccctcta aatagccagg gtttcagaca ccaagtcaaa tacataaccc 109500aaatcacaca tgcaaggcta gaaatacaca caatcactcg ttatcacaca cactgctaga 109560tacagtcatt tatattaata caacctcagt cacacactca gacatggttc tgcatacgca 109620accactgtca tacacaatac tgtcacacaa ccccagtcac

acagatacaa tgtgacttca 109680gacacaatgg cagtcacaca ggcagagttg cacagacagg tgtgtgtcac tcacgtatat 109740aaaatcaggt agagacacaa ctataaacat tgtcagtcac tgggagggtc acacatgcac 109800atggagccat agacaactcc actcacacac agtcacaact ccacccacgt cctgtcagtc 109860acacgcatgc ccacccccag actcaacaca tactgtcaca tacccagtta tagttaccga 109920ggcatacaaa cacagggtca caaaagacac aatcacagac aaccacagtc acaaccatgc 109980acacctccaa acacagacag actaaaaagt acaggattct gcacagtgag cagctgtcac 110040acacacatac acagtcacac agatactagg gtcacagaca caatcataga caccaccaca 110100agcacacaca cacgacacag gattcctcag tcaccagctg cagcgtacgc gtgcacacac 110160acacacacat acacagccac agtcacacaa acacagggca cactcctagc cacctcccca 110220tcgcttgctt ccccccttcc ccccaggtac cacacacaaa gccgccgtca ccgtcaccgc 110280agacactgca gacagacagg gctgcacccg gtccctgggg agccgccccc agcccagcct 110340gtatcctgga gcctgagggc caggtccagg agggggaagc ggtgcattgt ctgcgggtgg 110400ggccactctt ggacagctgg gcagccctgg ggacaaaggg ggtggcctag ggatcctgtg 110460ccctgggacc catgaccaag ccagggggtg gagggattgg gggttgcctg aaattgtcct 110520tattttattc aggctggggt ggggtggagt cccaggcaca gggaccttgt tttgagaagt 110580ggctgtgcct gggactccgc ccaaggattg gggggatgct gtgcccaggg tgcctctgag 110640acctgggggc aggctgtgct tggagtcccc ctaggccttg gcgtggtggg aacgctgtac 110700ccagtgaccc catcctcgag accgtaccta ggcagttgtt gtgctgagac ccccttaggc 110760agggagaggt agggattgtg tctggaatcg cgtcctggag gccttggttt gatacggggg 110820ctgtgtcccc gaccccatct ccatccccat ctagttctag gagttgtacc tagaatctct 110880gtacccctgt ccttggtttt gtggggggtc tgtgtccagg atccctattt ccagggcctt 110940ggcaagagat ggcccagggg tctgtgccca agaccccggt ctcctgggct ttggcttgtt 111000gggcctgttc ctggaccccc acccgggacc accctctcca gccttggcac cctctctcca 111060tccgggcgcc gcggccgcct cccaccctcc gccacatcag cagcggcgcc gcccccgacc 111120cgagcccccc tctcccgccc ttctcacgct ggccgccgcg ctgcgggaca tccagggccc 111180gggcgccccc gcctcccgcg gccctggctg ggcctggctc cccgactgct gctgctgcgg 111240tggtggcggc ggcagctcgg tctgacgccg gccagggccc ggggccgggg gatggtgcgg 111300gatgcacgcg cgcgagcctc ctcggctccc gggaggattc cgttccgggg gcgggggagc 111360gtccctcggc ctcggctccc cgccccgacc ccgcccattg gcccgccgcc tgccgtatat 111420gcagaaaggt cccgccccgc cccgcccctt ggcctgaaga ccccgcccac acgcagacac 111480catcccgcct tccccggcgc ggccaccgcc ccgccacgcc cattggccag tcccgagctg 111540agcatgccta tgaacatcgc cgagtccttt cccccggtcc gtcctggcct gggctccctt 111600tccctccgtg acacctgacc tcagatcccc tccagctccg cgtccgaaag agttgcttct 111660agaggcgcct tgccgcccca cacccccaaa tcttcccgct aaccccatgg ttccccagcc 111720cggcgggggc gggcaggagc ggtgacgagg cactttttgc aaggaagggg agggggtgtg 111780aacagaccaa ggcgtcctga tgcgcgatcg gttcggcttt gggaacgggg gcgccggggt 111840gggaccaggg cgcggttctg gccgctacgg cgcccccgcc gccccctacg ccaatcctgt 111900gggtttggca aagcagctgg cagggacatt agagcccatt agtaaaggcg aggttgccag 111960gagtgagggg agggagcccg cagccaagag gcactgtgtg tgtgggaggc ctcagctgcc 112020acagccctta gagcaggtgg tcagcacgtg ggggggggtg gggaaggcga gaaggaggtt 112080cccggcaaca gatggcacag gcagggctga ggctttcaga caagggggtg caggggggct 112140ggccatctgc acctggaggc cgctggcgag ctcctccccc tctcccccca accctagcgc 112200agagaaaaga gctgggggaa ggggagggct gcttttattc cgattgaaga ttcagctccc 112260ccccaccccg cacccctacc tctccaacac actgagaggc tggaacccgg gagaaggcag 112320ctgttggagg agcgagggag gcagaggtga ggactgcctc caggaccatc tcgccttcca 112380cgggaggctt gaggcagagg tgagggctcc ccctgatgag tctgatctgc ataacgacat 112440gcagcggccc aaggctccct caaatgttgg caaagataag ttaaccgctt ccctggctta 112500gttttcggat acccactttc gagtggggag gtgcaggatc tagggcacga agttgggagt 112560tccccagccc cagggatcct gagctcctgg gccaaggagg agagccaggc aagactggga 112620agcccaaggg ggctcctctg acccagggca gacggggaag ggataagagg cactacagca 112680gggtacggcc tgctctgggg actgaatccc ccatggaggc tgtcatgagg gatccaccca 112740ggagtcccct ttggtgggga ggctgccggc agtggctgcg tctggctggc gactggccca 112800gtagcggtgg taggtgtcct ggaagaggtc cctgcaggcg atgtgggctc ggaggtgggc 112860acaggccagg aaagcccctg ccagcttgcg gtgcagggca taggtctcct cgggtggggg 112920acacagccgg tgccgcagca gcaccgggat gaggtcctgt atgcggcggg ccgtttcccc 112980cgacccaaag tcataagggc cctgggtggc gaaaggctcc cccaggatca tcactgcctc 113040cacgtgggcg tcggagaatg cctgggagtg ggggtggggg gagagcaaag gcagccagtg 113100tggacataga gccctctgca taacccagaa acaacgtgta gcctccactc cctccagtct 113160ccaccatcaa cacaagcccc gactccccca agagtgagca gcttccactc cttccagagc 113220ctggactaga caagcagctg cctattcccc gagtaagcac cccttacttc cctgcagagc 113280ctccaacaga caagtagccc tctactctct ctacaacaga gaagcggcct tcgcccctcc 113340tgaacagatc cacggtgccc atgttcccag ggttcctgag aagtcaggca gccacctccc 113400cccactcctc cccaaagccc ccagcatgga taagcatccc tcctagagtc acccactccc 113460caggtataga cacacagcct ccattctccc tagtggagac aagcccctcc tagagtcccc 113520cagtccccgg gtatcgacat gccccatcac ctactcgagt tcctcagtgg agataagcag 113580ccccccactg caccccacca acagacacca gcccctttct cccccagtgt ctccccacct 113640tggtttcaaa gcctgtgagg aatttgaggt ccctggactt ctgcaggaca cagtctctgt 113700ctccatcagc tgcagccttc accacctggg gagacgggtg ggagttagag ggacaaaggc 113760cggggctcaa gggggctctg gagaagagga gctggaagcc tgggcctccc atgtacccac 113820ctccattctc atctgcctgg gccctccctc acctggaagc ttcctgctcc caactttgcc 113880tgtctgtgac tcccttaaag actcttccag agcctgggag tggaggtggt tagggatcct 113940gcccacctag agggcaatgt ggggcctgcc cgggaactgc cacagtgaaa cagtgcaaga 114000aacaagtgtc agggctgctg gtgagtccaa acactcaact ggacgggtat gagcgtgacc 114060cagaactgca tccaaagttg ccaggggcca tctctctgtc tcccacactg gactttgagc 114120cccgtgagag caaggatccc agttgggttt agtcgcacgg ggcacagggt ctggtgctga 114180ggaggccctg ggtgaacctt gctttagcaa atgagcgtgt ggagcagagc agctctccag 114240ccatgagctc acacacacag ggcaggagtt gtgggcatgg agagatgccc agctggggcc 114300agctggctag ggttccgtcc cagctctgcc acctgccggc ctgttgggcc tccactttct 114360catctgtgaa gtggggatgc caaaagtgcc ttcctcatgg ggctgttggg aggataaaga 114420aggtgatgcc tgtggcctgc ctggcgctgt gtctcatgca ggaagcaccg taaatactat 114480aatctaccat tattaagagg tgggcacggg ggtccctatt tcacagaagg ggaagcagac 114540ccggagtagg gagtggaacc gggtcacacc actcactact gggttgccct tttttgtgag 114600gagggggatt cgggattaat tccattccct ctctgctccc cctgcccgag catgtctggc 114660catctgtcag gcctgtggtc ctcagaagcc agggctttta taaagtggca aaggctgcag 114720gcctgggtgg gaggggaggg tgtcagtggg gagaagaagg gtctcagctt tgtgcctcag 114780tggccggcag agagggcccc aaggggcctg tgtgtaaggg gttatcacct cctcttcctg 114840ttcctgtctc agaggtggcc ccaccagtcc ccagaccaga cccctagaca cctctgtccc 114900caacttctag cccgtctgct cccatggact gccagctggg catctcccag ccacccctct 114960gcccctctcc acagctgccc tgagctccca cccccaggct tagagaccac ttcttattca 115020gagggagttt tcaaattctg actgcatccc ttccctgctc aaatcttttc cacggctccg 115080cagggcacct ggatacagta cgagctgtag agcgcagcct ctaaaatccg cagtgatttg 115140ctgcagcctc gtcactgtgc tgccccccga cctgccctcc cactcagaat gggagcttcc 115200tttgggtgct ctagggcctt actactacca gtgtggtccc catacgggta gccctggcct 115260cacatgggtg cgtgtcagaa catagcatct tacacccacc tccagaccag aatctgcact 115320tgcacaggat caccaggctt cacatgcaca tccaagtctg agaaatgctg ctctaatggg 115380actgtccctt atcactgcct cgtcttggca catgttgtct atctgaaata ccctccgagc 115440cttttcccag ttggcccccc tcatccctca ggtctcaatg ctgacactcc ctcctccggg 115500aagccctcct tggctcccca ggctggctca ggctcctcct ctgggctcac agtgccctgc 115560gcttccccca tcccagccct gtccatgcta ggtcctcact gtcgcctcac tgactatgag 115620ttctgtgagg aggggcctag gctgggccca ggtcactgct gtgtctccag ctttgcctag 115680aatagagctg ggcacagagg aggggtcaga aaacatttag attggctggg caggagggct 115740catgcctgta atcccagcac tttgggaggc caaggcagga ggatcacctg aggtcagcag 115800ttcgagacca gcctgggcaa catggtgaaa ccccatctct actaaaaata caaaaattag 115860ccgggcgtgg tggcacatgc ctgtaatccc agctactcga gaagctgagg caggagaatc 115920gcttgaaccc aggaggtgga ggttgtggtg agccaagatc gagccactgc actccagcct 115980gggcgacaga gcaagactct gtctcaatta aaaaaaaaaa aaagaaaaga aaaaaaagga 116040aaagaaaacg tttagattga tggctacatg attagaggac ccagggcaaa tgtccaatct 116100caacaacgaa tgaaatggta ttctctgcag cctctaagac aaactgaccc cagtgggtgg 116160gagagacgag ccaagtacgt gaggaaacac ctcctgtaga cagagttgcc cccagggaca 116220cacacctggg ctggacacca gggccctgga cagcatgggg tctggagagg tgacaagatg 116280gtcactgtgg gcctttctct taggagggag ctgggcagtg gttggaagct tgggctctgg 116340acctggacca cctgaatttg aatcccaagt ctgctgtgat cttgggcacg tgacttaacc 116400cctccaggac ccagttactt catctggcct aaaacgggcc taaaaacggt ccttttcgca 116460ttgtgttgct gtgtggttta tatcggttcc tatacgtaag cactaaagat ggagcctgac 116520atattaagtg cttggtgtgt gctagttgct acgagtatta ctattattta ttatttctta 116580attccagaaa ctgcatttcg ccttcttact cctctgcctc agtatatggc ttgagcctca 116640gcctttcaga ggccctgggg tctgggggag actcacctcg atgtaatggt ctgtgaactc 116700tgtcccaaac tcccggcttg caccaaagtc cagcagggtc acctggaagc aaggaatggt 116760gaaaggaatg ctgggatccc attcacaccc tcactgtcta ttggggcagc caggatctgt 116820ctccctcccc atgaccctgc ctgctcctgc cagagtccct gcctggctgc ctcactgggc 116880tcctggcctc atctcccgtt tccaaccgac cccctagctg aaggcttttt tttcttttag 116940ttctaattgt ttatgcaata acaaatttta gacccagaaa aaaaatccag agaataataa 117000aagatataga aaagtaaaat gaatactcac aaatcctgcc acccagccta aaatataaaa 117060tactccccat ccggccacac gtggtggctc acacctctaa ccctagcact ttgggaggcc 117120aaggtgggtg gatcatgagg tcaggagttt gagaccagcc tggccatcat ggtgaaatcc 117180cgtctctact aaaaatacaa aaattagcca ggtgcggtgg tgcgtgcctg taatcccagc 117240tacttgggag gctgaggcag gagaatggct tgaacctggg aggtggaggt tgcagtgagc 117300cgagattgtg ctattgtact ccagcctggg caacagagtg agactccgtc tcaaaaaaaa 117360aaaaaaatac tccccatcca cgtggagcct cctgtgtatc ccgccctgat cacacctccc 117420ccaggtcccc agggtcacct ctttcctaca atcattatta aattatttcc tgaaattctc 117480atttatgcat ttctatattt tctatgtatg tgtacagctg taaacaatct agagtaatgg 117540tgtgcatatt ttcaaacttc acagaagtgg tatttactgt cgttctcctg caacttgtgc 117600tttttgccca gcatggtttt gcgatttatc cctgttgcca tgtgtcgctc cagctcagtc 117660actcatttca cactgctgtg taaggacttc gttgcgtgaa tctatcacag tgcatttatc 117720tggctgagga atactgtggt tgtttctgat tttttttcct tctttttaaa tatgtttatt 117780agttataaac tctgttctga catttttttt tttttttgag acagggtctt gatctgttgc 117840ccaggctgga gtgcagtggc acgaccatgg cttactacag cctcaaactc ccacgctcaa 117900gtgatcctcc cgcctcagcc tcctgggtag ctgggaccac aggtgcaccc caccacacct 117960ggctaagttt gaaacatttt ttgtagagat agggtttcac tacgttgccc agactggtct 118020cgaactactg ggctccagtg atcctcccac ctcagcctcc caaagtgcag agattacatt 118080agtgagtcat ctcacctggc ctgtttctaa tttttgtgct caatgaacac ctgtaagaat 118140gtttctaggg cagtagagtt tgaactgacc acaacccaca gtaagaaatt gtttctactg 118200gtggctgggc gtgatggctc acacctgtaa tcccagcatt ttgggaggct gaggggggcg 118260gatcacctga ggtcaggagt tcaagatcag actggccaac atggtgaaac cccacctata 118320ctaaaaatac aaaattagct gggtgtggtg gcgcacgcct gtagtcccag ctagttggga 118380ggctgaggca ggagaatcac ttgaacccag gaggtggagg ttgcagtgag tcgagattgt 118440gccactgcac tccagcctcc attctcaaca agagcaaaac tctatctcta aacaaacaaa 118500taaataaaat tatatatata tatatatata tatatatata gagagagaga gagagagaga 118560gagagtttct actgggcgtt catgcaaatg cacacaaaaa cgtcaaacaa aagtgtccca 118620aggccaggcg caatggctca tggctgtaat cccagcactt cgggaggcca aggcaggcgg 118680atcacctgag gtcaggagtt cgagaccagc ctggccaaca tggtgaaacc ccatctctac 118740taaaaataca aaaattagct gggcgtggtg gcaggcacct gtaatcccag ctacttggga 118800ggctgaggca ggagaattgc ttgaacctgg gaggcggagg gtgcagtgag ccgagatcac 118860accattgcac tccagcctgg gtgacaagag cgagacttca tctcggggaa aaaaaagaaa 118920agtgtcccaa aataatatgg atccctccca tctgtgacat actgacatca tctattccat 118980aaaaaaaaaa aaagtgctgg tggatcatga ggtcaggagt tcaagactag cctggccaaa 119040atggtgaaac ctcatctcta ctaaagatac aaaaaattag ccaggtgtgg tggcgggcac 119100ctgtaatccc agctacttgg gaggctgagg tgggagaatt tctcgaaccc cagaggcaga 119160ggcttcagtg agctgagatc gtgccattgc actccagcct gggcaacaag agcaaaactc 119220tgtctcaaaa aaaaaaaaaa gtcctgttgg aaaccaataa attgatgtca ggactcctat 119280cacttggagt tgggtaaaca tatccctggg gtatgaacct aggaggggac acagggtgta 119340tgcacattgt ggagaaagaa gaggcaaggg actagggctg gagactccgt ggggccacag 119400gatgctcagc aaagggttca gacttgattc tgagggggct gtgaagctgt aggagggata 119460tcttgaccag atttgtgctt tagaaagacc cctctgggga caaaatgggg atagaccact 119520ttggaaaaca gttggcaacc cctgataaag gtaatgatgt atccaccaac actcaagtct 119580gcaggtccaa accttcacta caggtctttg tacaccccct gccctctgct gggaacactc 119640tgctctctgg atggttgtct ccttttcccc tgtcccatct cagccttttt ttttttttta 119700aatagagccc aggctggttt taaattcctg gcctcaaggg atcctcctgc ctcagcatcc 119760caaagtgctg gaattacagg catgagccac catgctcagc ctctggtctc agcttttttt 119820ttttttcttt ggtgagacag agtctcgccc tgtcacccag gttggagtgc agtggcatga 119880tcttggttcg ctgcagcctc gacctcctgg gctcaagcca tcctcccacc tcagcctctc 119940agtggcctca gctttaatgg cacttgcttt aagaagcctc ccttaatccc tgctcacccc 120000acagtgagtc aggcactttc cctgggatcc cataacttcc tgtgcctccc ccaactccag 120060cccccacccc tctgcctgtg cctcccccat cccggtcctg acccatctgg cctgtgctcc 120120tcattgtggt tggtacgaac cactctaggt catcgctgtg tggtgccagg tccccccact 120180ggactgggca ctctgagaag gcaagggtca gggatgtctt tttattgctg tcaagaggca 120240agggcaggtg atggtgtgtt ctgtatggat gacgagtgtg gtagtgatgg ctaactgcct 120300tccaaaagct gtacttcccc tctgtgctgt cacattgcca ccaggaacca ctgcctagcc 120360agggactcca ttttccagca tgccttgcac ctaggcaggc tatgtcacta gctctcactg 120420atggaatggc aacggaagtg ctatgtccat tgccccagga tgagcttagt gtatttagcc 120480tgggcattac tttttccact tctggccaaa gcagttaggc agggggctac cctcaacctc 120540tcttaccctt tccttgggaa gcagagcgtt gcaaggcccc agggatggca aaaccacaaa 120600agggaaggag ctgggtccct gaatcccact tggaaaaggg ccacccctgc ctattgtggg 120660ggtaatcaac tgctattttg ttgagctacc gaaatatcaa ggaatatttg ttacaacagc 120720aaatgtaccc agacacacat cactaggaac caacctggtg gctggaggca tcatacagga 120780agttggccca gttggggtca gtctgcatga atcggaactc aaacagctcc cgcagacaca 120840gcgtcaggag ctggaagcaa atctggggtg gggagaatta acaggcatct cagtgtgatc 120900tcccttgtgg tgccactgct ggcctggaga gagaccatga gcctggccca cccgccctgg 120960ggccatgccc ttcccactgt gccaccagac agcatacctg gttccgcagg tcctggctta 121020ggccctggca ctggtccagg gggacccctc cagccagctc catgcccagc acccgtgtcg 121080tgcacagctc cttaaccacg gctgggaccc ggaagaaggg gtcatttgcc agcagctgcc 121140tggggcagaa ggaaagggag gaaggggact tcgtgcttca ggcttgtgac ccagcttgag 121200acctcctcct tgtgctctca gaagtcctcc atgaacagtc tgcgccatgc cctccctcct 121260gcccatctct tgctgctgtc tgccctgggt gatgaccaac acctggctgg actgagattt 121320aacaagtatc tccaaggtgc ctactctgca cctgcctctc aactgggtgc tgctggaaac 121380ccagtcacca cttccctacc cgaaaccctt ctatgacttc tggttgcccc agaaggatga 121440gttcaggtgt atttcagcct ttgcattact ttttcattaa tttattaatt cattcatccc 121500aaaagtagtc actggtatca aaatctgtga agtctatagt gatacccatg ggtcagtcct 121560tgcaatcact actctgaaca caggtaaata gcgggaaaga atcttctgtg tccatccttg 121620tgctaaatga tgctggggac agagcagtga atgaaccagt ccctggacct ggcccccaac 121680cccgagacca cactctcaca aacagacgga ttatagattg aggtaagtgt gttggctggg 121740tgcagtggct tacacctgta atcccagcag tttgagacac cgaggtggga gaatcgcttg 121800agcccaggag ttcaagacca gcctgggcaa catggtgaaa cctcgtcttt atgaaaaact 121860acaaaaatta gctgggcgtg gtggcctgcg cctatgttcc cagctactca ggaggctgag 121920gtgggaaaat cacttgagcc tgggaggtcg aggctggagt gagctgtgat ctcaccactg 121980tattccagcc tggaaaacag agcgagaccc tgtctcaaaa aaataaaaga agtatgtcta 122040tgtaagattt gggaggcaga gaatatgagc aaggtctctg gttgaggatc cgtgggatgg 122100ctggaggaga gtgagggaga acaggagggt ggtgtggggt tttatcctaa gggcacccgg 122160gaatcctgtg ggggacgggg gggtctctgg cccatcaccc cacttcacac tctcttcctt 122220gagctcctcc tttggggttt gtatttttgt ccttgttgat aaaaatctct gatgtttgaa 122280ctgctcctca tgaaccggag ccatgtgggg catttaatcg gcacactccc ctttcatcct 122340cactccacag tgaggggatg ctctctggag gccactgtac agattgtatg gatgcaggcc 122400acgtaacctg ttaagggctg acccaggatt tcatcccgca tctgagtcta gggtgtgtgc 122460ctctaaccac tgccttctac tgagctttca ctctctgtct acagagcttg gcacgtttta 122520ggctgtcaat aaatgtgtga gccacactgt ggaggacccc actgaggtgc cattaattgc 122580tacacatcag gatgcttcca agatataacc acattgttcc acgtagccat agttcatgca 122640ttttcactgc tacgtaatat tccacagatg aatataccgt tgcttatttg tccaccctgc 122700tggataaact tgatggatat gggttgtttc cagtttgggg ctgttgcaga caagcgttct 122760agaacagtct gatgatggat actggcaaaa gggtccctag agtgttcagc agggagggca 122820atcgttggct tgcagagttc ttgaatataa gggcttatgt gatgatgcca acctgttctc 122880aaaatgcttc taccaccttc tcccacaacc tgcagtgcag aagggatgct gtggagccca 122940ctctctctac ctcccagtgc tgtgggctcc ttgctctccg tcagtccagc agaggtaaga 123000gtgtgtcatt gtgtaattaa ttaagtgcct gtgtcggacc acagtggata tgcggcccat 123060ctgacacagg agaagactgc cgcttgggaa gtgacctgcc caagctcaca gaggacaaag 123120ggggtaagcg aagtgatgga tgagtggaag gatggatgaa caatgattga aagaaagaga 123180gagtttgccc taccccacag ctccagctgc cagaagctga gggggcagct acttcccacc 123240cagcctggga gggagggaag gagggaagct cagggcactc agctcacctg aaattctggg 123300cacaagccgc ctcacgacgg tagtcacact cccaagccag ctcctgctgc aaggcctgca 123360ggctctgctc ggcaaacagg cctgtggggg aggtgtgtca gccagggaag ggccccgagc 123420gcccactggt ggatgccttc tcctgccaac cctctctctc ctgtctcccg cgctgtccct 123480cacagctcct actctaggcc tgtgacccac atctgtccct ctcctgtctc ccacgcagct 123540cctgctcctg cctctgacct gcatctgtcc ctctcctgtc tcccccgctg ccccttgcag 123600ctcctgctcc aggcctctga cctgcatcgt atcatctgtc tacacatttc cctcgtcctt 123660catagcacca cagggttccc cggggtcttc cgaagccttt tctgggctct gtctcttgca 123720catgcctgca ccccagtccc tggcagctct ttcagagtca cgcctgcctc tattctgtct 123780ccttttcata ctgactctca cgttgctcac tgcatctgaa tctcacttct gggcctggct 123840ttccctctcc ctctccgtct cttacacaaa cacaacccac cctcctttct ctaggcgcct 123900cctcacgtgc catccccagg actgtccttt tctgctctgc cgcacctaca atcccgctcc 123960ctgcatgcac accctctgag agtctgctgc tgtatcttgg ccctgggctc ccgtctctct 124020aaggctctgt taaaatccat aaggcttttc ccacacctgc tcatgctccc tgggctctcc 124080ccgccttggt gtcctttctg tctctgacac tcccgctcac aacgccagca caccctgccc 124140gtgctctcct ctgggctccc cctcctgctt tctctctctg ggcatagccc ctttgggagg 124200tcagcagagg agtgggtggg cgcctcaccc gcgggcaggg ccgcgctcat cttgagtacc 124260gccagcaggt tctggacatc gctctgaatg ctctgggcta tgccggggta ctgtaaaggg 124320agaagggagg gagagaaggt gggagtcact tctctgggct agcagggtgc ccgcccctac 124380cctgcccagc ctcccctctc acctggatct tcacggccac ctccgtcccg tccctcagca 124440ggccctggtg cacctgccca attgaggcag cggcaaaggg cacctcctcc aaggaggcca 124500ccttggcctg ccagtccctg ccgagctcct cttcaagaac tctctgcggg gagtggtcac 124560agccatcatc attgtggcag agttcattcc ccaggctgag tgctttacgt gttgataacc 124620ccagcactca ccacatgcag ggccctgggc taagctcttg gctgccaccc cctttgcaga 124680tgaggaaact gaggctcaga gagagctccc ttgtgcaagt

gactagccag gcactggcag 124740actgtgaggc tcagcctagc ctgtgtcccc tgaacctgga ctccctgggc tgttgtgggg 124800attgctatta tttatagtta agactcataa caatcctttt tttttttttt tttttgagac 124860agggtcttgt tctgtagccc aggctggagt gtagtggcac tctcacggct cactgcagca 124920tcaacctccc gagctcaagc catcctcctg cctcctgaat agctgggact acagatatgt 124980gccactgtgc ccagctaatt attactgtta ttatgtttag tagagacaag gtctcactat 125040gttgcccagg gtggtctgga agtcctgagc tcaaatgatc ctcccaccgc agcctcccaa 125100agtgctggga ttacaggcat gagccattac acgtggccaa ccatccttta ttatgctctt 125160atatgttatt attaactcac agttactgtg atcaagaaga gctaaaattt acaatgggct 125220tcctgtgggc caggtcctat tcagagtggc ccagagagag gcagtacctg cctggggccg 125280catggcgaat aagcagaaca gggatgggag agcaggtggg tggcggaatc ctggattcca 125340tgccttaccc agttattaga acagctcatg tcctgggcac ttacttggtg ccaggcgccg 125400tgccaaccta ttacagacac gatctccttt aattaaaaaa acagtaataa tcacagctaa 125460cacctgcatg ttgctcacag tgaatcaggg gccgttctca gtgctcagtg taaactgatt 125520tatgtgaccc tatgatgtgg gtgtggctgt cactatcgcc atttcccagg gaagggaact 125580gaagcacaga gaggtcaggc tgctgttccc tgttttaatc accacagcaa tgctaggagg 125640tgtgtactct ggtgattccc attttacaga tggggaaagt gaggctcaga ggcagggagt 125700ggggcagtga agccaggaag gtcaggcagg tcagaggaga tggagcctgc ctccctcacc 125760gccctccccc actgggcact caccagcatc tgccagcggg gcatgaagtc ggcgctctgg 125820cggacccgct caaagatgtg ctgcagctga gggctgatga agctgttgtc ttgggagaca 125880gtggaaccag gggggaagta agcgaagagg tgaggaggga ccccgtgtga gtatctgaag 125940ttggggcctg ttggtgggta gggctggggt agaagggagg tcaggggtca ggagtcgagg 126000gtcatgctgt accctggatg ctgagcatct ggccaacctt gagggcggcc cctcgaactg 126060tacataaggt ctgcacaatc cgctcggcat tggcctccga caggaagggg ctggagtcca 126120gcccagaacc accctctggg gagagaacaa ccattagaat tataaccaca aatatcatca 126180ctgcggccag gcccggcggc ccacgcctgt aatcccagca ctttgggaga cccaggcggg 126240atgaacacag gagtctgaga ccagtctggg caacagtgac atcctttctc tattaaaaaa 126300aatatatatc atctgcacac caacaggaat ggctaaaacg aaatacggag gccaggcttg 126360ttggctcgcg cctataatcc caacactggg aggtcaatgc aggaggatgg cttgagtcaa 126420ggagttccag accagcctgg ataacaaagc aagaccctgt ctctaattag ctgggtgtat 126480ggtggcatgt gcctgtagtc ccagctactc aggaggctga ggcaggagga ttgcttgagc 126540cctggaggtt gaggctgcaa tgaactgtga tcgcaccatt gcactccagc ctgggcaacc 126600aagcaatacc ctgtctcggg aaaaaaaaaa aaaaaagaaa agaaagaaag aaaaataaac 126660ataagttaaa acaaattgca ggagagtcaa agagtaacta ctacagtatt gaatagatga 126720gctatcacta cacacaacag cccaggtggg tctcaaaaat gtaatgctga gtgaaagcag 126780ccgggtgcat gaaatcatca cccagttaca ctgatataaa gagcaaaaca aggccaaaca 126840aatccagggt ccaggagcca agacagaggt cacccttggt gaggggagtg accaggtggg 126900gacatgagaa gggcaacgat tctcgaaatg tgggccaggg acccctgagg gtccctgaga 126960ccattcagag gggtctgaga gatcaaacta tttttatcgt aacattaaga tgttattttc 127020ccctttctgc tctcatgcgt ctaagaacat tcactggagt tctccagagg ctccaggaca 127080tgtgaggaca ccatcagact gacagctgat ggaatgtgta cgtgtgtact cttgtgtttt 127140aaaaatatct ctgtattttt gttgtgtttt tgagacagtg tctcactcta tcacccaggc 127200tggagtgcag cggcacaatc atggctcact gcaacctcct gggcccaagt gatcctcctg 127260ccttaacctc ctgagtagct gggactacag gtatgcacca ccatgcttgg ctaatatttt 127320tactttctgt aaaaatgggg cctcgctatg tcactcagac tggtctcaaa ttcctgacct 127380caagggatcc tcccgcccca gcttcccaaa gtgttgggat tacaggcgta agccaccgca 127440cctggcctaa aaatttctca gttttaattt ctaatatggt agacattgat aactataatc 127500cacataaata agctctttgg aggctcattc taacagtttt attgagaaat aattcacata 127560ctgttataat tcaccattta agttatataa ttcaatgatt attagtatat tcacagagtt 127620gtgcaagcat caccagaatc aattttagga cagttacacc acgcaaaaaa gaaacctggc 127680tgggagtgct ggctcatgcc tgtaatccca gcactttggg acgtcggggc gggatcactt 127740gagttcatga gtttgagacc agcctgggca atatggtaaa accctgtttc tacaaaaaat 127800acaaaaatta gctgggcatg gtggtgcatg cctatagtcc cagctactca ggaggctgag 127860gcaggaagat cacttggacc caggaggtag aggttacagt gagccgtgat cccgccaccg 127920cactccagcc tgggtgacag agtgagacct tgtctcaaaa aaagaaaaaa aaaaaagaaa 127980ccctataccc attagcagtc actcttcatt tcccccaatc tccccaggcc ttgacaacca 128040ctaatctact ttatgtccct acagattttc ctattttgta catttcatat taatggaatc 128100attcaatatg tggtttttca gtgtgtggtt gcttttactt agtgtttttt ttttttgaaa 128160cagtgtctcg ctctgtctcc aaggctggag tacaatggca tgatcttggt tcactgcaac 128220ctccgcctcc ccggttcaag caattctcct gccttacccc ccacccaagt agctggggtt 128280acaggcaccc accaccacat ccagctaatt ttttgtattt ttagtagaat caggatttcg 128340ccatattgga caggctggtc ttgaactcct cacctcaggt gatccacctg cctcggcctg 128400ccaaagtgct gggattacag gcgtgagcca ccgcaaccgg cctcacttag tgttttcaag 128460attcatctac attgcagcat gtgtcagccc ttcattcctt tttatggctg gataatattc 128520cattgtatgc ctatcacatt ttattcatcc attcatcagt tttaaaggtg tgcagggatc 128580ctgagaccaa gaagtttgag agcagctatt ctagggtttc ttactctggg tacggacaaa 128640tgtactttgt gaaaacgcac caagccatac acttacaggt atgtgtacct gggtttatat 128700gcaaattaca tttcagcttt ggcaaaacat ttatttttct ttttttaata tgaacacttt 128760atgaatttat gtgtcatctt tgcacagagg ccgtgctaat tttctctgtc tcattccaat 128820ttttatttat atgtgatgct gaagcaagca cagcacaaca aagcaattct taagccttta 128880ttaattttga aggccagttg tggtggctca cagctgtaat cccagcactt taggaggcca 128940gggtaagagg atctcttgag cccagaagtt caaagctgca gtgagccatg actcaccact 129000gcactctagc ctgggtgaca gcaagactct atctcttaaa ataaaattta aaataaaata 129060aaatgttatt gagctcatta ttgagctgtt ccaggcagaa tcctaagtgt ctttgtggat 129120tctctggctg aatgcccaca atcacacctg gaagtaagaa ttatcaatcc tttaattttc 129180aaggtgagaa agcaagagac tcaaagaggt gcagcaccta tccctgggtc acatagcatg 129240gaagtggcag agtggggtgt agactcaggc tggtcatacc caaaccctaa tcctccacct 129300accctcaact ttttattttg aaaaaaatat ccaggctggg tgtggtggct catgcctgta 129360atcccagcac tttgggaggc tgagcaggga ggatcacttg aggctaggag ttccagaccg 129420gcctgggcaa catggcaaaa ccttctctct acaaaaaata caaaaaatta gccaggcgtg 129480gtggcacgtg tctataatcc cagctatgca ggaggctgag gtgggaggat cacctgagcc 129540tggggaagtc aaggctgcag tgagccatga tcgtaccatt gcattccagc ctgggtgaca 129600cagcaagacc ctgtctccaa aaaaaaaaag acagaaaaaa atccaaacag aaaagttgca 129660tgcataatat cgtgaacacc tgcacacccg cacaccctcc acctcgattc aacatggtac 129720cattctgctt cgtctgcttt atctgtgcgt gtacccacac acttactatt attatttttt 129780gctgacccac ttgcatgtag ttgcacttaa gctttgctaa gaataaggat attcccctac 129840acaatcacag taccataatc acatgtaaga aaattaacac caattcctta acatctgcca 129900tgcagtccat attcagattt tccatttgtc tccaaaaagt ctttcatggc tgttttttcc 129960aaactgatat gcaatcatgg ttcagatgct ccatttgtca aataatgtct ctttcatctg 130020tttttaatct ggaatatcca cccccacttg tttcaagaca ttgacttgtt gagggaacct 130080ccacctaccc tcaacttttt attttatttt ttataacggc aaatgctaca catctaattc 130140catctctgat gtacacagac cctcgctggc acttctattt tcagctttct gctcctgctc 130200caagttagga actcccaatg gcttaaatgt tttctcagat aatctaatat gtggctgggc 130260acagtggctc atgctataat cccagcactt tgggaggcca aggcgggtgg atcatgaggt 130320caggagttga agaccagcct ggccaacatg gtgaaaccgt ctctactaaa aatacaaaaa 130380ttaaccaagc gtggtggcat gtgcctataa tcccagctac ttgggaggct gaggcaggag 130440aattgcttaa acctgggagg tggaggttgc agtgagccaa gactgcgcca ttgtactcca 130500gcctgagcga cagagtgaga ctccatctca aattaaaaaa aaaaaatcta atatgcttct 130560cttaatcatg accctgatag tggtttaggc ctgttcaaag cacttcacaa tgactctaag 130620aggtgggtaa attatcacca cctccatctt ccgcatgagg aaactggagc tcagaggggt 130680gaagtcactt gccccaggtc acacagcaaa gccaggatct gaacccaggc agtgtggctc 130740actcacctga ctgcagacga cctcctggca tggacttctt agccatctcg gccagtactc 130800ctagccccaa gcccacagcc agtcctggag tgcaagagaa gaacatgagt gcccgtttgc 130860ctggggtgcc cccagcctaa cccactctcc tttctcagtt tttctccaag aatgcttgtc 130920tcccaactct ttttattttt tcttttgttt gagatggagt ctcgctctgt tgcccaggct 130980ggagtgtggt ggcacaatct tggttcactg caacctccac ctcccgggtt caagcgattc 131040tcctgcctca gcctcccgag tagctgggat tacaggcacg cgcccaccac gcctggctaa 131100attttttttg tatttttagt agagacgggg tttcaccgtg ttggccaggc tggtctcgaa 131160ctcctgacct caggtgatcc tcccgcctcg gcctcccaaa gtgctgggat tataggcatg 131220agacaccgca ctcagtcttg tctcccaatt ctttgtatct ctgtttccaa atcagtctct 131280gactctgttc ctgcatgggg ctccctttaa ggtgcagctt cctctttctt taaccctttc 131340tccatgtctc tgtctccctc ccagcagttc tcagccctgg ctgcacattc cagttaccag 131400aggagctccg gtaaatataa tgcccagact ccactcccca aattctgatt aaattggcct 131460gagacatggg aatttgtgtt ttgttaaaaa gcacctcaga taattctaat gtgcgatcaa 131520ggttaagaag gcccctcggc cgggcacagt ggctcatgcc tatgatccca gcactttggg 131580aggccgaggt gggcagatca tctgaagtca ggaggtcgag accagcctgg ccaacgtgga 131640gaaaccctgt ctctactaaa aatacaaaat cagccgggcg tggtggtgca tgcctgtaat 131700cccagctact caagaggctg aggcaggaga atcgcttgaa cctgggagac agaggttgcg 131760gtgagccgag atcacaccat tgcactccag cctgggaaac aagagagaaa ctccgtctca 131820aaaaaaaaaa aaaaaagaag gccccgaaac aattgtccta ggtccctctg tcttctggtg 131880actcttcttt ctctgtccac acctcctctt ctttatgctt atctcttttt ctttttagag 131940acagggtctc actctgtcgc ccaggctgga gtgcaatggc accatcataa ctcactgcag 132000cctcaaattc ctgagctcaa gtgatcctct tccctcagcc tcctgagtag ctgagaccac 132060acgtgcatac caccacgctc acctaatttt ttattgagac agggtctcac tatgttgccc 132120aggctggtct ggaactccag aactcacgtg atcctcctgc ctcggcctcc caaagtgctg 132180ggattacagg tgtgggctac caggcttgac ctctcccttt ctaagccagt tatttctgca 132240tctcttgcct tctccccatt tgtcctatct atctagatct ctttctctct tttcctccct 132300ttgatgttat ctctccatct ctgatttcct ctgctacctc tcctcttgtc cctaaagacg 132360tctcgggtct ctctccttct tttgttgtca ccatctctgt caattaccat atctggcatt 132420ttctgtgtcc tttctacatg tcaggggctg ttcccagtgc cttctgtgca cttactaatt 132480tttgtcctta catgaggtct ccaccttcat aaaatgtatt ttacagaaaa cttccatttt 132540acagaaaagg aaattgaggt tcagagaagt gaagtaattt gcccagagtc acgtcacaaa 132600gcgaggacac agcagagtca tcccttaatc cctgggcagc ctggtgccaa agctctaacc 132660agtgcctttg actgcctctg cagactgtga atctatctat gtatatatat atagattttt 132720tttttttgag acagagtttc actcttgctg cccaggctgg agtgcaatgg tgcgatcttg 132780gttcactgca atctctacct cctgggtaca agcaagtgaa tctatatttt taaaacttga 132840accaggcggg gcatggtagc tcacgcctat aatcccagca ctttgggagg ctgaggcagg 132900tggatcacga ggtgaggagt tcgagatcag cttgaccaac atggtgaaac cccatctcta 132960ctaaaaatac agaaattagc ggtcaggcac agtggctcac gtctgtaatc ctggcacttt 133020aggaggccaa ggcaggcgga tcatgaggtc aggagatcga gaccatcctg gccaacatgg 133080tgaaaccctg tctccctaag aaaaaaaaaa aaaaaaacaa caaaaaatag ttggacgtgg 133140tggcgtgcat ctgtaacccc cgctactcag gaggctgagg caggagaatt gcttgaacct 133200gggaggtgga ggttgcagtg agctgagatc atgccactgc actccagtct gggtgacaga 133260gcaagactcc atctcaaaaa caaaaacaaa aacaaaactt gaaccatgat cagcaataag 133320aagacattta cgttataacc agtgcagacc aaggtatatg tttcacgaaa caagactttc 133380ccttgctcta caggtgcatg catattttct gtcctattct tctttttaaa tgctggttgc 133440aacccactaa attatttcat gtgacttgca cgacatccgg ctgtgtaacc caaagtcaag 133500tgacctcccc tttgttagcc tcaatgtcct catgtacgga atagaacact cattgattca 133560gtgcagcatg tgtgtatatg ggacactgca cattacaggt tctcagtaaa tgttattatg 133620gccaggagca gtggctcatg cctagaaccc cagcacttcg ggaggccgag gcaggaggat 133680cgcttgagac caacttgagc aacataggga gaccctatct ctacaaaaaa atatttttta 133740aattacccag gccaggcaca gtggcttccc gggcaccgtg gctcacatct gtaaatccca 133800acactttggg aggccgaagt gggtggatca cttgaggtca ggagttcaag accagcctgg 133860ccaacatggt gaaattctgt ctctactaaa agtacaaaaa ttagccaggc ggccaggtgt 133920ggtggctcac gcctgtaatc ccagcacttg ggaaggctga ggcaggcgga tcacaaagcg 133980aggacatagc agagtcatcc cttgaaccct gggcagcctg gtgccaaagc tctaccactg 134040cctgacaaac atggtgaaac cccgtctcta ctaaaaatac aaaaattagc cgggtgtggt 134100ggatgcatgc ctgtaatccc agctacttgg gagtgtgagg caggagaatc ggcttgaacc 134160cgggaggtgg aggttgcagt gagccaagat ggcgccactg cactccagcc tgggtgacag 134220agggatactc cgtctcaaaa aaaaaaaaaa aaaaatagcc aggcatagtg gcaggcacct 134280gtaatcccag ctactcagga ggctgtggca ggagaattgc ttgaatgtag gaggcagagg 134340ttgcaatgag ccaagacggt gccactgcac tccagcctgg gcaacagagc gagactctgt 134400ctcaaaggaa aaaaaaaaaa aaattacccg ggcggatggt gcacaactgt ggtcccagct 134460actcaggagg ctgaggcgag agaattgctt gagcccagaa gtttgaggct gcagtgatcg 134520cgccactgca ctccagcctg ggtgacaaag tgagactctg tctcaaaaaa aaaaaaaaaa 134580attatcattt atgttcctct tgatttctct tggccttgca ggcccttgcc tttgtctctc 134640tttttttgtc tctctctctt tcctgtctct gattcatcct ctcccttgct tcaatctgta 134700aatgttgccc tttctaattg aggtcacacc aagatccccc aaagtcacac ctacccccaa 134760agttggccaa gcggctgatg cgggaggcag gcaccttgcg ttctcgagag cggtcactca 134820gctgggaaat ggggacaagg tctgagggtg ggaaagtggg catcgtggcc agagagtgca 134880gccactctgc caccacaccc ttccccaagc tcagggggcc agcagtattc gtggggtgtt 134940gctgggtggg tgggggtaat gatacctggg gccggggtgt cttcctggga cgggcctccc 135000gtgccctgcg aatgtcctcc tcacccaggc ctctcccagg cccatcctgg taaaactttt 135060gggcccaaga acctccacat ggtccctgca agagatatac tttgataagg aggggaggac 135120atgggatcac ctggcccttc tggacccctc ctgtcctttt accctctgaa gtctccctca 135180gcctcttccc cttggggacc tgctccctag cctcttaccc agcggtgggg cccaggcccc 135240agggccccac aaggccaacc aacagtctgg cccagctgtc caccggtccc ccgaagtagg 135300ccccccacct tcagccacat tgcctggagg agaagaggag ggattattca ggtgggagtt 135360gcctggcttc ttggccaggc ccccatgttc ctctgtgtcc accctctctc attcccaccc 135420actaaatact tcctccacta ttaatagatt cccacagttt ctcctggttc tcccctggtt 135480gctaggaacc cttagctctt cctgcaggcc tcccaaaacc cactttcccc cctctcccaa 135540ccctcgccgt tgctagggtc cgcccccgtt actagacacc cacagttcct caggggctac 135600ctctccactt ctctgaaacc cccctcgttg ctatgcaccg ccttcccctc tgttggccct 135660gtaggcaccc gcaattcctc cggtgtcccc ccgcccgatc cccaccccgt tactgagcac 135720ctccccccgt tgctaagcac ccactgctct cagcctccga gtccgcaacc tgctggggcc 135780ctcctgtgct tccgggagcc tctgtatgcc cgcccccttc ggccagccaa ccaatggcgc 135840ggcagcaact cgctgactgg cacggagttt ctccatctgt gcgcggggga aggggccaga 135900gagaggccct agcgatggag cctggaatta aggtgggcat cgggggccca tctgggggga 135960ttgctgaggc atcgcgggag cgcaagcgtg ccctgtctgc ccttccactc acctcaaagt 136020gccttgtacg cgacagaccc ttctgttccc tacactttct tgcaaagtct cccttacaaa 136080cctgacgcct ctcttctgca cgaatatctt gccaaccccc cttcttattt ttacccctgg 136140caggctcaac acaattcctt tgaatacaca ttcttcccag caaacatttc ccttgcacat 136200ggagcccctc cactttgcac aaacacccac attctggcac ccaacctcct tccttgtgca 136260tataaatccc ttgccttgct tgccaactgt ttcccgctca cgccttcaac tctctcgtgt 136320acataccctc ccccccactt gcacactgag tctctgttcc ctcacacacc ctgttctctc 136380cgctccccgc ccacctgcgg aatggtgcga ctgggagccc tctgcttcct gtaggcctga 136440catttcccag aacacactca gccaagattc ccagtgctga gtcaggaacc ttggcatccc 136500agaaaaccac ctcccatcct atctttcttt ctctgtgtgt gtgtgtgtgt gtgtgtgtgc 136560gcgcgcgcgt tggaaagcct gctctcccca caacaggctg actcacccac ttctcacagt 136620ctggaataga ggcatctggt tggggcatct ttcccaccac tgggagaggg agggatgccg 136680atgcttcccc cacagaaccc cgctgcccca acccctcttg tcgggaatca ggcctctttg 136740tctctattcc cgtactgtgt gacctcagaa aagccctcat ccctctctgg acttctcctt 136800cccaacctgt atgaggtact aggtgggctc ctgccttcga tttctctcat tggtctgtga 136860aaaggtgact cattttagag ccttggacct gtgcccaatg tctcccccag ttgactcaat 136920ttcaagacaa accacctcct ctcccccttc agaggtgaac ggctgactca ggagctgggt 136980ggcagctcag ccttgggggc aaaatatatc aaaatcacct aggacaataa ataatcctac 137040tgggctacaa ctgacagtgc caggcccggg gccacatgct tcacatacat gagatcatgt 137100cagatagccc cgtagctgca agcaaagggt agaggccggc agatctctga gcctctgttc 137160tcacgtgtaa aatggagccc tggcatccct attgttcagc cttggagaat gaactgaaat 137220cgtgtcaggg tctgatacag aacaagtact ctatacatga cagagatttc ttacggaaaa 137280tccaatggag cgtaagtcat ttgctcaggg tagcggagct gggaactggc agaggaaggt 137340ctcgaaccca cacccgtggg aactccaagt ctttgaaagt ccgtcccgcc cctgcgtgaa 137400gaatgggcgc gcggctggac tcgtcaccgg gggttttagg gaaggttgaa cttgtcattc 137460aaccgtgtag ggagggtggt ttagtcacag gggtggaggg agggggccca ctggcgcgcc 137520accaggaccc cggtgcccta gatgcatacc tggccgcgct tcggatgctc agaggcaaac 137580cccctcccct tgggaggcgg agtcggacaa ggctccgtct cgttccgttc cgtcacgtcc 137640ggtggggcgg ggcttcgggg ctttcccctt tgaggggagt atcggttaac ccttgcgcgg 137700cggggcgggc tggagctccg cgggccggaa cccgggagtc ggggctcccc agccacaccc 137760ctcgcgggat ttaaagggat aggaggggcc gggtcggccg aagcccgaac cgaaggagcg 137820ggcatgaggc gctgcccgtg ccgtgggagc ctgaacgagg cggaggccgg ggcgctgccc 137880gcggcggccc gcatgggact ggaggcgccg cgaggagggc ggcggcggca gccgggacag 137940cagcgacctg ggcccggcgc aggggccccg gcggggcggc cggagggggg cgggccctgg 138000gcccggacag aggggtccag cctccacagc gagcctgaga gggccggcct cgggcctgcg 138060ccggggacag agagtccgca ggcagaattc tggacagacg gacagactga gcccgcggca 138120gctggccttg gagtagagac cgagaggccc aagcaaaaga cggagccaga caggtccagc 138180ctccggacgc atctagaatg gagctggtca gagctggaga cgacttgtct ttggacggag 138240accgggacag atggcctttg gactgatccg cacaggtccg acctccagtt tcagcccgag 138300gaggccagcc cctggacaca gccaggggtt catgggccct ggacagagct ggaaacgcat 138360gggtcacaga ctcagccaga gagggtcaag tcctgggctg ataacctctg gacccaccag 138420aacagttcca gcctccagac tcacccagaa ggagcctgtc cctcaaaaga gccaagtgct 138480gatggctcct ggaaagaatt gtatactgat ggctccagga cacaacagga tattgaaggt 138540ccctggacag agccatatac tgatggctcc cagaaaaaac aggatactga agcagccagg 138600aaacagcctg gcactggtgg tttccaaata caacaggata ctgatggctc ctggacacaa 138660cctagcactg acggttccca gacagcacct gggacagact gcctcttggg agagcctgag 138720gatggcccat tagaggaacc agagcctgga gaattgctga ctcacctgta ctctcacctg 138780aagtgtagcc ccctgtgccc tgtgccccgc ctcatcatta cccctgagac ccctgagcct 138840gaggcccagc cagtgggacc cccctcccgg gttgaggggg gcagcggcgg cttctcctct 138900gcctcttctt tcgacgagtc tgaggatgac gtggtggccg ggggcggagg tgccagcgat 138960cccgaggaca ggtctggggt gagtgggacc catcctgccc ttgagccaca tcacgcaaaa 139020ctccttattc ctccgccttt gcttaggaag ttctctaccc atttactgtt agttgcccac 139080cagcaatttc atctccggga acctcttcca tccactgacc tcctccctct gacagccagg 139140ttactaattc actccaggca ccccttctta attctctcct ttccccttcc tgcactgtct 139200ccactcctgg gggtctacaa tggagggcca ctgaccgact ttatggggcc caggaacccc 139260tgaaattgta ggactaagga gcctgccgtg cgtgttcaca tacattgttg cagcgacggt 139320ctgacatctg tctaatcctc tggaatctga agaacactgg gatagggaga caggcagggt 139380gcactttcta ccccacattt cttaatctgg ggcctgtggc tgtcttaaag ggtcacaaac 139440cttcaccacc ccttagccta tttgtatgta catttttcta gggagcaaag cgattccccc 139500agcttgcatc agattcgcaa aagggctgtg tgaccccaaa cgccaaagga tccttggcct 139560agccgggagc ccacctggtc tcccctgtga cccctacatc cccaaggagc cccctgaaca 139620ctcttgttta ctttgtccac cgtcaccccc agcttgggtg tggctctccc ctggtgaatc 139680aggaggaccg gccgggcagg ttcagggagg gcgggacaga gcagaggccg gtgtgaaact 139740ggagagcctc acgtggggct gggagccgtg gggctgggag

ccgagtccgg agtccatcag 139800cttgccagct tgcctgctga ggcctctttt tgctctgggg cccctggctg gagtctgccc 139860tgagccccgc ttcaccccac atgccttcct tggggacgtg ttcacacatg tggccctagc 139920tgtgagagac agacctgcct tgacgtgcct gtgcctgtgt gcaggggctg accctcctgg 139980gccccattgc ttttttctct ctgcctgccc tctcacttcc ttggcatctc agaacagctg 140040agctggaagt gggtgaataa taataataat aataataata ataacaacaa caattagcac 140100tcactcatgt ttagccctgt gctaagtgct gtgcttttat taactcactc actcctcgca 140160gcaaccctaa tgaggtagat actttttttt tttttctgag acagtctcgc tctgttgccc 140220aggctggagt gcagtggtgc catctcggct cactgcagcc ttcacttcct gggttcaagt 140280gattgtcctg cctcagcctc ctgagtaggt gagacaccag gtgcccgcca ccacacctgg 140340ctcatttctg tattttgagt agagacaggg tttcatcatg ttggccaggc tgacctcaag 140400actcctgacc tcaagtgatc cacccgcctc agcctcccga agtgctggaa ttaccagcat 140460gagccactgc acccggctga ggtagatact attattatcc ccttttacag atgaggaaac 140520tgaggcacag agaattcaag tcacttgtcc aaggatatca ccttgcaaga tgcagatcaa 140580ataattctaa tccttactgt acaccagaca ctgttttaag ttttttcttc tttttttttt 140640ttagtctttt ttgtcaattt ttttctgtca ttttttatct taaaatagca tctatcttaa 140700ttaagggctt tgtatgtgtt aactctgagt ccttatgaca gcactgagat tgtctccatt 140760caacagatgg gggccaggct cagtggccca agcctgtaat cccagcactt tgggaggccg 140820aggcaggggg atcacctaag gtcaggagtt caagaccagc ctggccaaca tgatgaaacc 140880ctgtctctac taaaatacaa aaattagcca ggcgtgtgat ggcgggcacc tgtaatccca 140940gctacttggg aggctgaggc aggagaatcg cttgaatgtg ggaggcggag gttgcagtga 141000gccgagattg caccactgca ctccagcctg ggtgacagag caagactcgg tctcaaaaaa 141060aaaaaaacaa aaacaacaga tggggaagct gaggcataga gaggtgagag attctttgct 141120tagggttggc cacgtcaagt cagagccagg attctaactc agttctggct gagtttcaaa 141180cccatcgttt aaaccctcca gtgtgtagat ctgttcctaa cttgtctccc tcccaggcct 141240ccctatctcc agtttttttc tcatccttcc agaatctgcc tccatggccc agctttgtct 141300gctcaggtgc cctctctgag agcagtcagg ggctcagtgc tgcgtttgga gcctccggtc 141360tccaggcgcc ttcccagaat cgacttcctt ccctcctcct gaccccctct gctgtaacta 141420ggcctgagta cacactgttc cttgaacact cttctgttgt cctgcctcca cgcattgctc 141480aagccgttcc cactgcccag catacccgtg cttccttctc ccttaatttt gaaatcctct 141540ctgaccgtaa aggctcagct tcctttctcc ctttcctcct tccttccttc tcaccatcct 141600gtcctttttt taaaattgtg ttctctttct ttttcttttt ttggtaggga tggggtcttg 141660ctatcttgcc caggctggtc ttgaactcct gggctcaagt gatcctcctg cctcagcctc 141720ccaaagtgct gggattacag gtgtgctatc ctattcttct aatgagacaa aaatcactcc 141780ctaagcccct accatgtatt tggtcctatg ttagctttgc tggggaaaca gcagtgacca 141840agacactcat ggagctccca ggcccatgaa agagacagac caatcagccg acagtcacag 141900ttcagagtgg tcaggaggat gtgtgagccc agaaggaggt cactggccag acacagggta 141960tcagagaggg cttcctggag gaaggggcat ataagctgag accattgtga aaaaaatccg 142020agaaagccca gataaaccat tggatctaac tttttttttt tttttggagg gcgtgcagtg 142080cggagtttca ctctgttgcc taggctgaag tgcagtggcg agatctcagt tcactgcaac 142140ctcagcctcc cgggttcaag tgattctcct gcctcggcct cccaagtagc tgggactaca 142200agcgcacgcc accacgcccg gctaattttt ttttttagta gagagtgggt ttcactatgt 142260tggccaggct ggttctgagc tcctgacctc aggtgatcca cccacctcag cctcccaaag 142320tgctgggatt acaagcatga gccactgtgc ccggcccgga tctaacataa aacagagaga 142380gaagatatta tgtttatgat taaggggcca ggtgtggtgg cttatgccta taatcccagc 142440actttgggag gctgaggtgg gaggattgcc tgagcccaga aatttgagac caccctgggc 142500aacacagtga gacctcatct ctactaaaag gaaaaaagaa ctagctagat gtggtggtat 142560atgcctgttt tccagctatt cgggaggcta aagcaggagg attgcttgag cctgggaggc 142620agaggttgca gtgagccaag atcacacctc tgcactccag cctgggcaac agagtgagat 142680cctgtctcaa aaaaaaaaaa aattactatt aaaaaaatcc caactaacat tcttcagtcc 142740aagcatcaaa gaatgtttct ggagcgtctg tcgtgtgcca ggccatgtgc tggggacata 142800atcataacca tgacaacccc agtctctgcc atcatgagct tgtagtccag caagtgtgta 142860ggggataagc cccaaggcac tgggatccaa ccagagctag aaccccagcg ctgtgtgggg 142920tgatgttagg taagtggctt cacctctcag accctctgtt tcctcctttg taacaccgag 142980acgataatct ccctggggtt gtgtttttag aaattaagta ggttgtggca cactgagtct 143040ttgtcattgt gtctggaatg ttccaggtac ttagtaaaca ggaaccttta ttaatcatct 143100cttccccagg gccggcagct ggattgggga gggactagcc cttcccgaac cctgactccc 143160tcttaacctt cccactgtca aagagatgtc tgtgaggtag ctgggctctg agggggcggg 143220agagatgaac acgtccctga tcctggggta ggagagggat gagccataca gtttccttct 143280ctggaggtga cccactcttc cagtacttgc taagggactt gacatgcttg tggggtgcag 143340aatgtattcc tgtgtgtgta tgtgttcatg aatcagacac taaccctgtc tcaaaaagct 143400catagtttag tcggcatgat acaacgaaaa ccctgttttc tatttgcttc tctggttttc 143460tttctttctt tcttattttt ttgagtcagg gtctcactgg gtcacccagt ctggagtgca 143520gtggcacaat cactgctcac tgcagcctca ccctccaggg ctcaagtgat cctcccacct 143580tagcctcctg agtagctggg actacaggtg cacaccacca cgcctagctg attcttaatt 143640ttttatttat ttatttattt attttttgag atggagtctc gctttctcgc ccaggctgga 143700gtgcagtggc acaatctcgg ctcactgcaa cctctgcctc tcaggttcac accattctcc 143760tgcctcagcc tcccgagtag ctgggactgc aggtgcccgc caccatgccc agctaatttt 143820ttgtattttt agtagagacg gggtttcact gtgttagcca ggatggtctc aatctcctga 143880cctcatgatc cgcctgcctc agcctcccaa agtgctggga ttacaggcat gagccactgc 143940gcccggccta atttttaaac attttgtaga gatggggtct tgctatattg cccaggctgg 144000cctcaatctc ctgggctcag tggtcctccc accttggttt cccagtgttg agattacagg 144060cgtaagccat cgtacccgct gcttttgtgg tttcctttgt tctctctctc tttgtctact 144120tctgttcatc tttttctttt catcattact ttgtatctct ctcttttagt cttcctatat 144180ttgttttgtt ttttttttgt ttttgagaca gtcttgctct gtcgcccagg ctggagtgca 144240gtggcgtgtt cttggctcac cgcaacctct gcctctcggg ttcaaacgac tctcatgcct 144300cagcctcctg agtagctggg actacaggtg tgtatcacca cgcccggcta atttttgtat 144360ttttagtaga ggtggggttt caccatgttg gccaggctgg tctcaaactc ctgacctcag 144420gtgatctgcc cacctcaccc tcccgaaatg ctgggattac aggtgagagc caccacaccc 144480ggcctatttc tttatctttt agcaattcta tacctgtctc tgtattagtc agggtaggtc 144540aggattttct gcagtaacaa agagccccca aatcttagtg acttagaaca acaaaggatt 144600attttgcttt atactacaca ttggtcacag gtcagtggtg ggtcaagggc tctgcttcat 144660gctgtcttca ctcagggtcc caggctgagg gagcttccat ttcttttctt actccctccc 144720ccactgggga acaaacgtgg cgagtcataa actggctctt aaggctccta cccgaaagtg 144780acacttctgc tcccagttaa ttggccaaag caaggccagg tgtggtggct cacacctata 144840atcccagcac tttggagacc aagatgggag gattgcatga ggccaggagt tcaagaccag 144900cctgggcaac atagcaagat gccataaagt agctgggcat ggtggcacac gcctgtagtc 144960ctgactactc aggaggctgg gatgggagca tcgcttgagt ccaggagttg gaggttgcag 145020tgagctatga tggtgccatt gtactgcagt ctggctgacg gagtgagacc cggtctctaa 145080aacaaaacaa aacaaacaaa aaacaacaat ccccagttca ggagggcagg gacatccctg 145140aactaatagc tggagctatg tggtgaacag ctgtcatgac tgccacggtc tctgtcgctg 145200tctctgtctc tctgtcatca ctatgtcatc tgcctctctg tttctgtctc tctctgtggt 145260ccatctccat ccatcaactc ctgcctctat aattttcccc aaaaggtctg acctggttta 145320gggacagaga tggggcttcc aatatttgac actggtccct acataatggc ttatgcctga 145380aaccccaaca ctttgggaga ctgaggcagg tggactgctt gaggtcagga gctcaagacc 145440agcttgggca acatggtgaa accccatctc tactaaaaat acaaaaatta gccagacatg 145500gtggcatgca cctgtagtcc cagctactcg gagggtgagg caggaggatc acttgaacct 145560cggaggcaga ggttgcagtg agccaagatc ataccactgc actctggact aggtgacaga 145620gaccctgtct caattaaaaa aaaaaaaaaa agaagatttg gaactgtgta tgtgcagtgg 145680aagatgtaag ggttgtttgt taaaccacaa caaaacctag cctgtcctta ctcataagat 145740ccttactcat aagagaagga cagagagaca tagatacaaa gaaagtgatg acagagggga 145800gaaatgggca aagaatttcc cctatcttgc tgagggcttt gggcgatcat gtgattgccg 145860aactaagtgg ggctcactca ccccaacaag cctgggaaca gtgatcccag gaagcccctg 145920gccctggaaa gactgcaggt cccctttcgt tccctctcat ggcagcacct ctagcccctg 145980ccttccctgg ccttggccct gaccccaccc tgctctgctc cctacagagc aaaccctgga 146040agaagctgaa gacagttctg aagtattcac cctttgtggt ctccttccga aaacactacc 146100cttgggtcca gctttctgga catgctggta agtggggtgg tggtggacag agctgggcag 146160agtctcctgg gccagggaaa gggatgttct ctgtagttta gttcccccac ctagtgatgg 146220gcttggtgac agtccccacc ttatgggact gttatgggca gtgcttaggc ctgggcctgg 146280cccttcgtat gtcagggcag agggctattc cttgttattc tggtggagag agggagcttc 146340agacggacct gagctcaaac cctagttctg ctctgtattc atgggtgacc ttgggcaagt 146400tactttcctt tactgggcct cagctgcccc atctgttaat gtggagataa ccttacctcc 146460cttgcaggat taaccgaaga gttaaaatca aaatgtatat aaagattgag gccaggcacg 146520gtggcttaca tctgtaatcc tagcactttg gcaggccaaa acaggaggat cgcttgagcc 146580caggagttta agaccaacct aggcaatata gtgagacccc gtttcaatta aaaaaaaaaa 146640aagattggct gggcgcagtg gctcatgcct gtaatcccag gcctttggga ggccgaggtg 146700ggtggatccc ctgaggtcag gagtttaaga ccagcctggc caatgtggtg aaatcccttc 146760tctactaaaa ataaaaaaat tagccaggca tggtggcggg tgcctgtaat cccagctact 146820caggaggctg aggcaggaga atcacttgaa cccgggaggt gaaggttgca gtgagccaag 146880atcgcagcat tgcactgcag cctgagtgac aagagcgaaa cttcgtctca aaaaaaaaaa 146940agactgaggc acaggactct tatgaatgga aatgatcact ccttgccttc tccgcgtgtt 147000cagagcatag caggccttca gtaagtagca gctgtaacat tttgccccca ggaccttgca 147060aatgcctgca gcacagagta gcacaatggt ggcatatagt gctcttttga aaggctaggc 147120cataaatatc ttaggttttg tgggcctatg gtctctgtcg caactactca gctctgctgt 147180tacagcagga aagctgccat agacactatg taaacatatg agtgtgtctg tattccaata 147240aaactttatt tgcaaaaacc agcagcaggc tggactagaa aagtgtgccc attggcaaat 147300ggcgacagta agagaatttg tctgccttgt ttgtctttag atctgacctg gaaataaggc 147360aagaccccct aaaactgtgt caacacaagt ttgccatcta tatgtgttct ggttactatt 147420gctgagttta ttaaaaaaac aaaactcagc agagcacagc ggctcatggc tgtagttcta 147480gcactttggg aggctgaggt gggaggatca cttgagccca ggagtttgag accagcctgg 147540gtgacatagt gagaccttgt ctctacgaaa aataaagaaa ttaactgggc atggtggcat 147600gcacctgtgg tcccaggtac ttgggagctg agggtgggaa gatcacttga gtccaggagg 147660tctgggatgc agtgagcctt gatcgcacca cagtactcta gcctagatga ccgagtgaga 147720ccctgtctca aaaataaata cgccaggggc ggtggctcac gcctgtaatc ccagcacttt 147780gggaggccaa ggcaggcgga tcacgaggtc aggagatcga gaccatcctg gctaacaaag 147840tgaaaccccg tctctactaa aaatacaaaa aattagccgg gcatggtggc gggcgcctgt 147900aatcccagct actcgggagg ctgaggcagg agaatggcgt gaacccggga ggcggaggtt 147960gcagtgagcc gagatagcac cactgcactc cagcctgggt gacagagcga gactctgtct 148020caaaaataaa taaataaata aaataaaata aaataaatac aaaacaaaac ccaaaaaccc 148080caagacttag tgatggttaa aaaaaataac ttagtagaat aaaacaatca ttttattgac 148140ctcagaagtt ttgggtcagc aattcagaca ggatggcagg gatggctttt cactgctcca 148200caatatctgg gaactcagct agggacacct ggaggctaca agctgaaaac ttttggaggt 148260tcattcactt gcatgcgtgg tgattgatgc tggctattgg ctggggtctc agatggggct 148320gccacgtggc tttgccatgt agctccttga gcttcctcac agtatggtgg cctcagagta 148380ctcagatttc taacaagaca gctcaggact accttgaagg taagtgtctc tgccaacaga 148440agtcatgcag tagcacttct gccataaacc gtcccatatt taatgggaga gcaatctatt 148500ttttatttat tcatttaatt ttgagatagg atctcagtgt tgcccaggcg ggagtgcagt 148560ggtgcagtca tagctcattg cagccttgaa ctcctggcct taaaggatcc tcctgcctca 148620acctcccaga gtgttgggat tataggcatg agccactgca cccagcttgg gagagcaatt 148680aagagtatac tccttgatgg gaaaattcta taagagcagg atcaggaatg ggtctgagac 148740ccactgtgat caggagatac tgttgtagcc aactttggaa aatgtaatcc aggctggaca 148800taatcacagc actttgggag gctgagatgg gaggatcatt tgaggccagg agttcgagac 148860cagcctgggc atcatagcaa cactacccca acccgacatt acacattttt tttttttaga 148920ttagctggga gtggtggggg tgcacacctg tagtcctagc tactctggtg gttgaggtgg 148980gaggatcacc tgaatctagg agcttgaggc tgcagtgagc tatgattata ccactcaatt 149040tcagcctggg tgacagagtg agatcctctc aaataaaaaa agaaaaagaa aatataatct 149100gaaaatacag ctggccacta gaagaaatta gaattattat aatctataca ctctgcgtgg 149160tccaggaaat gcttgatcta taaattaact taaataggcc ctggttgtta gcaccttggg 149220attccaggca gcagcaaaag caaatccact ctggagagtg acgctctgga cttagatctc 149280acagaattcc cacagatgat cacatgtgta caatcaaaaa ttacaaaaca aattaggata 149340tcctgtgctg ggaacaggac ttggtttaag caacagagaa cagaaattcg ccctttcctt 149400accaacccct gggcaagact tttaagagtt gcggcctggg cacagtggct cacgcttgta 149460atcccagcac tttgggaggc caaggcgggt ggatcatctg aggtcaggag ttcaagacca 149520gcctgaccaa caaggtgaaa ccctgtctct actaaaaata caaaaattag ctgggcttgg 149580tggtgtgcac ctgtaatccc agctacttga gaggctgaag caggagaatt gcttgaaccc 149640gggaggcgga ggttgcagtg agccgagatc gcaccattgc actccagcct gggcaacaga 149700gtgggactcc atctcaaaaa aataaaataa aatcttaaaa tcattaaaaa aaaagttgca 149760gggagagaaa gcattgcagg agggtcgggc aagataatgg tggccaggat ctgatgcaaa 149820caggcagctg cggagaggtt ctcttcctga tccagttcct gatcctctca tttattctac 149880cacctttagg gaacttccag gcaggagagg atggtcggat tctgaaacgt ttctgtcagt 149940gtgagcagcg cagcctggag cagctgatga aagacccgct gcgacctttc gtgcctgcct 150000actatggcat ggtgctgcag gatggccaga ccttcaacca gatggaagac ctcctggctg 150060actttgaggg cccctccatt atggactgca agatgggcag caggtggggc tggggcagcc 150120ctggggcagg gatggagggc agggggtggg cattattgaa aatattggcc tggccaggcg 150180cggtggctca cgcctgtaat cccagcactt tgggaggccg aggctggtgg atcacctgag 150240gttgggagtt ccaaaccagc ctgaccaacg tggtgaagcc ctgtctctac taaaaataca 150300aaaaattagc caggcgtggt ggtgcatgcc tgtaatccca gctactcagg aggctgaggc 150360aggagaattg cctgaacctg ggaggtggag gttgcggtga gctgagattg agccattgca 150420ctccagcctg ggcaacaaga gtggaaccct gtctcaaaaa aaagaaaaga aaagaaaaga 150480aaatagcgcc aagtccattt tcaaagtggt tgtaccagtg taccttccca ccaccatgta 150540tgagtgttac agtcgtccca gattctcacc ggtgcttggt actgtctgtt ttattaactt 150600aaaccattcc gatgggtttg gaataggatc cctttttttc ctctttgaga cagagtctta 150660ctctatcgcc caggctggag tgcagtggca cgatctcggc tcactgcaat ctccacctcc 150720tgggtttaag tgattctcct gtgtaaacca agtagctagg attacaagcg cccgccacca 150780cacctggcta atttttgtat tattagtaga gatggggttt caccatgttg gccaggctgg 150840tctggaactc ctgacctcag atgatccacc cactacggcc tcccagaatg ctgggattat 150900aggcgtgagc caccacgcct agtctgcaag aagtgaactc taattgcttt ctccagctgg 150960gttcagtggc tctcacctat aatcccaaca ctctgggagg ctgtatacac acacacacac 151020agacacacac acacagacac acacatagtc ttcaactctc ccatttcatt cttttagtag 151080tcttttgata aacatatttt tataaacaaa atagtatttg tattattact cttttttgag 151140acagagtctc attctgttgc cccgactgaa gtgaaggagc atgattatag ctcacagtag 151200ccttgaactc ctgggctcag gcggtccttt caccttagcc tccagagtag ctgggactat 151260aggtatgtcc caccaggctt ggctatattt tattttttat agagacatgg tctccctgta 151320ctgcccaggc tggtcttgaa cccctgagct caagtgatcc tccttcttct gccccctgag 151380tagctgggac tgtaggtgca tactatcaca cctagctaat tttcaatttt ttgtagagac 151440aggctattta ggaaaagctc tgaatccatg cttttccgtt ctcacaccac tgccacaaca 151500atgagagcac agaagacttc tgtgaccaaa tgtttaggtt ttttaacccc acacaccaag 151560caacggacac cagctggatg tcctccaatt caagtctaaa accatctacc tggaaatagt 151620gtcagatccc acaggttggg gactcagtcc ccaagactgc cccccagtta cagacaccag 151680tcataagttc aggccttcga aacttctgac tgattggctc caagttggag ttcccatgtc 151740ctcctctttg ggttcaaata atttgctgga gtggctcaaa taactcaggg ggatacttac 151800ttacctttac tggtttaata taaagcaggg gtccccaacc cctgggccgc agaccagtac 151860cggtccatgg cctcttagga acggggcccc accgtaggag gccagcgagc attaccgctt 151920gaactccacc tcctgtcaga ctagcgggca ggagattctc tggagggcga accctattgt 151980gaactgtgcc tgcaagggat ctagattgta tgctcctatg agaatctaat tgatacttga 152040tgacctgagg tagaagagtt tcatccagaa accatccccc tcacagtctg tgggaaaaat 152100tatcttctac aaaaccagtc cctggttggg tactgctaca aaggatactg caaaagatga 152160agagaagtgt agggcaaggt atgggggaag gggtacggag cttccatgcc ctccctgggc 152220gcaccacgct ccaggaacct ccacagggtc agctatctgg aagctcctga gcccaatcct 152280tggttttttt tttttttttt ttttttttga gagggagtct tgctctgtgt cccaggctgg 152340aatgcagtgg cctgatccgc ccgccttggc ctcccaaagt gctgggatta gagatgtgag 152400ccaccatgcc cagcctaatc cttgggtttt tatggaggct ttaagacacc agcattcctt 152460cccccagagt atagggtggg atcctctctg gggagggtcc taagacccac agtcaggaag 152520gtggggaaag attagagtcc tgccttgggg caggtgaaag gagggcagga ggaggtcaga 152580gattttggtt tcttgagcca gcttctgaga tctaacacac ctaaaattat aacaaaagat 152640tgtggctggg cgcagtggct catgcctgta atcccagcac tttgggaggc caaggcaggc 152700agatcacttg aggccagttc aagacaagcc tgggcaacat ggtgaaactc tgactctact 152760aaaaaaatac aaaaatgtgc caggtgtggt ggtatactct tgtaattcca gctactcagg 152820aggctgaggt gggaggatca cttgaacccg ggaggtccta gaagttgcag tgagccaaga 152880tcacgccact gtactccagc cttggtgaca gagcaagact ccatctcaaa aaaaaaaaaa 152940aaaaaaggct gggcgtagtg gctcacactt gtaaatggga ggcagaggca ggccgatcac 153000gaggtcagga gttcgagacc agcctggcca acatcgtgaa accccatctc tactaaaaat 153060acaaaaaatt atccgggtgt ggtggcgggc acctgtaatc ccagctactc aggaggctga 153120ggcaggagaa tcgcttgaat ccgcgaggca gaggttgcag tgacccgaga tcaccaccat 153180tccattgcac tctagctcgg gcgggcgtca aaaaaaaaaa aaaaaaaaaa aaaaagattg 153240taacaagggc tatgagagtt accagccagg aaccatagag ggaaaccaat atacattgta 153300actaacaccg ggtctcgcta tgttgccgag gctgatcttg actttctggg ctcaagtgaa 153360cctcctgcct tggcctccca aagtgttggg gttacagatg tgaacactgc acctggccct 153420acctttaatt tagtccagtt tgtcagtttt tttcattgtg tttaagaaat cttttcctac 153480tccaagatca tgcaaatatt atgttttctt ctacaagctt tattgtttta gctttcatat 153540ttagacctac attccagata gaattaatgt ttctgtgtgt gggaggtagg gatcaggttc 153600atttttttcc atatggattg ttgacccagc actgtttatt gaaaagactt ccctttcccc 153660actgaattgc agtgcctagt cataactgca caactctacg tgtgtgtctt tgtggactct 153720gttgtattct gtgcattgat ttgcccattc ttgtgccaca ctgtggcttt atgtcttaat 153780atcaggaagg gtaagccctc cagtttgttc tacataattt cctttgtcac atcctctgtg 153840tgctcaggac ctatctggaa gaggagctag tgaaggcacg ggaacgtccc cgtccccgga 153900aggacatgta tgagaagatg gtggctgtgg accctggggc ccctacccct gaggagcatg 153960cccagggtgc agtcaccaag ccccgctaca tgcagtggag ggaaaccatg agctccacct 154020ctaccctggg cttccggatc gagggcatca aggtgaggac caggaaccgc ctggcctgtc 154080ccgggaaggc ctatagccag atcccaggca gggcttcttg gggaaagcca cgagagagtg 154140caggagacgg cgtgggatga aaggctgggg ctggggaagc ccagcctctt tcttacctcc 154200atacccatca gagcccaggt tctgtttatc cgtctgcctg agcatctcct gagtccatct 154260tttcctcctc tccttctcca tggtcatgtc ctagtccagc cccatcttct cctgcctctg 154320tctccctggg catcctggcc ctggtctccc tgcagcacaa gagctggagg gatccctttc 154380ccccagctat ggagaaggtt tctctttttc tttcttgcat tcctttttct ttgtcaaatt 154440aaatataatt gtatgaatag gccaggcatg gtggctcatg cctgtaatcc cagcactttg 154500ggaggccaag gcaggaggat tgcttgaggc caggagtagt tcaggactaa gctggccaac 154560atagggagct tctgtttcta gaagaaaaaa aaattgtttg aatagctagt cacacagttc 154620aaaagtcaaa ataatattat aaaagggtaa atgtggagaa atttctctcc caactctgct 154680gctgtccttc ccattctgtc cctctatccc tctacctgct catggggaac cactttgtca 154740gtttcttgta tttcttcctg ttagtgccag taaatggagt tgtagatccg aaatgttcct 154800cagtacgcat actgattggt actttgctat tttcacttaa

tagtaacacc ctgcagagtt 154860ttccacatca ttccatagaa agcttcctct ttctgttttt ttttccccca cagctatgta 154920acactgtttt tgtgactgtg cctggtcccc tatagacaga cacctgggtt gtttccattt 154980tttgccatta gcaggcctca aagaatcact ttgtatataa gacattttgc aagtatgcag 155040attgagctgt agatttccag aagcaggact cctgggtcaa agctt 155085885PRTMus musculus 8Gly Phe Leu Pro Thr Arg Arg Pro Glu Pro Arg Pro Asp Pro Gly Pro1 5 10 15Gln Pro Glu Pro Arg Pro Arg Pro Glu Pro Arg Pro Arg Pro Glu Ser 20 25 30Arg Pro Arg Pro Glu Pro Arg Pro Arg Pro Glu Pro Arg Pro Gln Pro 35 40 45Glu Ser Gln Pro Arg Pro Glu Ser Arg Pro Arg Pro Glu Ser Gln Pro 50 55 60Trp Pro Glu Phe Pro Leu Pro Ser Ile Pro Ala Trp Thr Gly Pro Glu65 70 75 80Ile Pro Glu Ser Gly 85973PRTMus musculus 9Gly Phe Leu Pro Thr Arg Arg Pro Glu Pro Arg Pro Asp Pro Gly Pro1 5 10 15Gln Pro Glu Pro Arg Pro Arg Pro Glu Pro Arg Pro Arg Pro Glu Ser 20 25 30Arg Pro Arg Pro Glu Pro Arg Pro Arg Pro Glu Pro Arg Pro Gln Pro 35 40 45Glu Ser Gln Pro Trp Pro Glu Phe Pro Leu Pro Ser Ile Pro Ala Trp 50 55 60Thr Gly Pro Glu Ile Pro Glu Ser Gly65 701047PRTRattus norvegicus 10Gly Phe Leu Pro Thr Arg Arg Pro Glu Pro Arg Pro Asp Pro Gly Pro1 5 10 15Gln Pro Glu Leu Arg Pro Glu Pro Gln Pro Arg Pro Glu Phe Pro Leu 20 25 30Pro Ser Ile Pro Ala Trp Thr Gly Pro Glu Ile Pro Glu Ser Gly 35 40 451137PRTCanis lupus 11Gly Phe Leu Pro Thr His Arg Pro Glu Pro Pro Pro Glu Pro Arg Pro1 5 10 15Gly Pro Glu Leu Pro Leu Pro Ser Ile Pro Ala Trp Ser Gly Pro Glu 20 25 30Ile Ser Glu Ser Gly 351237PRTBos taurus 12Gly Phe Leu Pro Thr His Arg Pro Glu Pro Arg Pro Glu Pro Arg Pro1 5 10 15Gly Pro Glu Leu Pro Leu Pro Ser Ile Pro Ala Trp Thr Gly Pro Gly 20 25 30Ile Pro Glu Ser Gly 351341PRTHomo sapiens 13Gly Phe Leu Pro Thr His Arg Leu Glu Pro Arg Pro Glu Pro Arg Pro1 5 10 15Asp Pro Arg Pro Gly Pro Glu Leu Pro Leu Pro Ser Ile Pro Ala Trp 20 25 30Thr Gly Pro Glu Ile Pro Glu Ser Gly 35 40

Claims

1. A method of treating a patient having a transforming growth factor beta (TGF.beta.) superfamily protein-related disease, comprising administering a therapeutically effective amount of an agent that modulates proteolysis of latent TGF.beta. binding protein 4 (LTBP4) to a patient in need thereof.

2. A method of delaying onset or preventing a transforming growth factor beta (TGF.beta.) superfamily protein-related disease, comprising administering an effective amount of an agent that modulates proteolysis of latent TGF.beta. binding protein 4 (LTBP4) to a patient in need thereof.

3. The method of claim 1 or claim 2 wherein the patient suffers from a disease selected from the group consisting of Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury and colon cancer.

4. The method of any one of claims 1-3 wherein the agent is selected from the group consisting of an anti-LTBP4 antibody and a peptide.

5. The method of any one of claims 1-4 further comprising administering an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent, and a modulator of fibrosis.

6. A method of treating a patient having a transforming growth factor beta (TGF.beta.) superfamily protein-related disease, comprising administering to the patient a therapeutically effective amount of an agent that upregulates the activity of latent TGF.beta. binding protein 4 (LTBP4).

7. A method of delaying onset or preventing a transforming growth factor beta (TGF.beta.) superfamily protein-related disease, comprising administering to the patient an effective amount of an agent that upregulates the activity of latent TGF.beta. binding protein 4 (LTBP4).

8. The method of claim 6 or claim 7 wherein LTBP4 interacts with a TGF.beta. superfamily protein.

9. The method of any one of claim 8 wherein the TGF.beta. superfamily protein is selected from the group consisting of TGF.beta., a growth and differentiation factor (GDF), activin, inhibin, and a bone morphogenetic protein.

10. The method of claim 9 wherein the GDF is myostatin.

11. The method of any one of claims 6-10 wherein the agent is selected from the group consisting of a peptide, an antibody and a polynucleotide capable of expressing a protein having LTBP4 activity.

12. The method of claim 11 wherein the agent is the peptide of claim 21.

13. The method of claim 11 wherein the agent is the antibody of claim 20.

14. The method of claim 11 wherein the polynucleotide is contained in a vector.

15. The method of claim 14 wherein the vector is a viral vector.

16. The method of claim 15 wherein the viral vector is selected from the group consisting of a herpes virus vector, an adeno-associated virus (AAV) vector, an adeno virus vector, and a lentiviral vector.

17. The method of claim 16 wherein the AAV vector is recombinant AAV9.

18. The method of any one of claims 6-17 wherein the patient has a disease selected from the group consisting of Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury, and colon cancer.

19. The method of any one of claims 6-18 further comprising administering an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.

20. An isolated antibody that specifically binds to a peptide comprising the sequence set forth in SEQ ID NO: 5.

21. A peptide comprising the sequence as set out in any one of SEQ ID NOs: 2-5, or a peptide that is at least 70% identical to the sequence as set out in SEQ ID NOs: 2-5 that retains an ability to act as a substrate for a protease.

22. A pharmaceutical formulation comprising an effective amount of the antibody of claim 20 or the peptide of claim 21, and a pharmaceutically acceptable carrier or diluent.

23. A kit comprising a therapeutically effective amount of the antibody of claim 20 or the peptide of claim 21, a pharmaceutically acceptable carrier or diluent and instructions for use.

24. The formulation of claim 22 or the kit of claim 23, further comprising an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.