Compositions and Methods for Treating Glioblastoma GBM

Abstract

Methods of treating a malignant glioma in a subject are disclosed. The methods comprise administering to the subject a therapeutically effective amount of a viral vector comprising: (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c), said first polynucleotide sequence comprising SEQ ID NOs: 2 and 3; and (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter.

Description

FIELD AND BACKGROUND OF THE INVENTION

[0001] The present invention, in some embodiments thereof, relates to compositions and methods for treating malignant gliomas and, more particularly, but not exclusively, for treating Glioblastoma multiforme (GBM).

[0002] Malignant gliomas, the most common adult-onset neurological neoplasms, encompass a family of primary central nervous system tumors including glioblastoma, astrocytoma, oligodendroglioma, and ependymoma, along with the juvenile onset neoplasms such as juvenile pilocystic astrocytoma.

[0003] Malignant gliomas are typically characterized by over-expression of growth factors/tumor associated antigens believed to significantly contribute to the unchecked growth of such tumors. Various malignant gliomas, such as glioblastomas, exhibit epidermal growth factor receptor (EGFR) overexpression leading to increased aggressiveness and poor prognosis. Malignant gliomas may also display over-expression of platelet-derived growth factor receptor, a phenomenon which has also been correlated with increased malignancy and poor prognosis.

[0004] Malignant gliomas, the most common type of primary brain tumors, are aggressive, highly invasive, and neurologically destructive tumors which are among the deadliest of all human cancers. Of the estimated 17,000 new brain tumors diagnosed each year in the United States, about half are malignant gliomas. Malignant glioma cells produce very invasive brain tumors with infiltration of both white and gray matter. At the time of diagnosis, microscopic extension through much of the neural axis by malignant glioma is the rule. Such extension by motile invading cells underlies the incurability by surgery of most gliomas, even when they appear small and restricted in nature.

[0005] Glioblastoma multiforme (GBM), the most serious form of malignant glioma, are extremely aggressive brain tumors which generally arise in the upper brain (cerebrum), but which may also occur elsewhere in the central nervous system, such as in the spinal cord, cerebellum, brain stem, or optic chiasm. Low-grade gliomas, which include astrocytomas, oligodendrogliomas, and pilocytic astrocytomas, account for 25% of all primary brain tumors, and over time most of these low-grade tumors dedifferentiate into more malignant gliomas. Diffuse astrocytomas are predominantly located in the cerebral hemispheres of adults and have an inherent tendency to progress to anaplastic astrocytoma and (secondary) glioblastoma. The majority of glioblastomas develop de novo (primary glioblastomas), without an identifiable less-malignant precursor lesion.

[0006] Despite optimal therapy with surgery, radiotherapy, and temozolomide chemotherapy, the median survival of patients with glioblastomas is only 12-15 months. When these tumors recur, conventional salvage therapies produce minimal benefit, with only 8-15% of patients alive and free from progression at 6 months (6M-PFS).

[0007] Neovascularization is a major feature of glioblastomas (Maher et al., 2001, Genes Dev. 15:1311-1333). Angiogenesis activators are extremely important in tumor growth, as reflected by the fact that neovascularization must occur for solid tumors to grow beyond a diameter of 2-3 mm (Goldbrunner et al., 2000, J. Neurooncol. 50:53-62). One of the molecules that regulates this process is the vascular endothelial growth factor (VEGF). VEGF mRNA is overexpressed in the highly vascularized glioblastoma multiform (Maher et al., 2001, Genes Dev. 15:1311-1333). It has been demonstrated that the transfection of antisense-VEGF-complementary-DNA as well VEGF antisense RNA encoding vectors result in down-regulation of the endogenous VEGF and inhibits growth of gliomas in mice (Sasaki et al., 1999, Int. J. Dev. Neurosci. 17:579-591; Zheng et al., 2000, Acta Pharmacol. Sin. 21:211-214). A similar effect was observed upon the local delivery of the angiogenesis inhibitor endostatin (Read et al., 2001, Nat. Biotechnol. 19:29-34). However, this strategy has a cytostatic effect. It is effective in inhibiting tumor growth but not in actually eliminating them.

[0008] Bevacizumab (Avastin®) is a humanized monoclonal antibody that binds VEGF, preventing it from activating its receptors, especially VEGFR2, abrogating subsequent biologic effects. This drug has shown benefit in colorectal, non-small cell lung, and breast cancers, and is approved by the Food and Drug Administration for these indications. Several studies have now evaluated the combination of bevacizumab and the chemotherapeutic agent irinotecan in recurrent malignant gliomas and the results have been more encouraging.

[0009] In one phase II study, the combination of bevacizumab and irinotecan produced a response rate of 67% and 6M-PFS of 56% in recurrent anaplastic gliomas, and a response rate of 57% and a 6M-PFS of 46% in recurrent glioblastomas.

[0010] These preliminary findings have been recently confirmed by a large multi-center randomized phase II study of 167 patients with recurrent GBM who were treated with bevacizumab alone or in combination with irinotecan [Cloughesy T, Prados M, Wen P, et al. Society for Neuro-Oncology 12th Annual Meeting, 2007].

[0011] Patients receiving bevacizumab alone had a response rate of 20% and a 6M-PFS of 35.1%, while patients receiving the combination of bevacizumab in combination with irinotecan had a response rate of 34% and 6M-PFS of 51%. The median survival was 9.7 months for bevacizumab (Avastin) alone, and 8.7 months for the combination. In addition, treatment with bevacizumab was also associated with a significant reduction in peritumoral edema and the need for corticosteroids. As a result of these studies, the combination of bevacizumab with irinotecan is increasingly used for the treatment of patients with recurrent malignant gliomas.

[0012] Another agent proposed for the treatment of malignant gliomas is Aflibercept (VEGF-Trap). This is a soluble hybrid receptor, composed of portions of VEGFR-1 and VEGFR-2 fused to an immunoglobulin G1 Fc domain. Like bevacizumab, it is designed to deplete circulating VEGF, but has significantly greater affinity for VEGF than bevacizumab itself.

[0013] In addition, inhibitors of VEGF receptors have been proposed for the treatment of malignant gliomas. In a phase II trial study of a potent pan-VEGFR inhibitor, cediranib (AZD2171; Recentin) in patients with recurrent glioblastomas, response rates in excess of 50% were observed and the 6M-PFS was increased to approximately 25%. Studies with other inhibitors of VEGFR such as sorafenib (Nexavar), sunitinib (Sutent), vandetanib (ZD6474; Zactima), pazopanib (GW786034), and vatalanib (PTK787) in glioblastomas are also in progress.

[0014] In comparison with drugs targeting VEGF or VEGFR, agents inhibiting other angiogenic pathways have produced less success. Drugs that inhibit PDGF receptors such as imatinib mesylate (Gleevec) were ineffective, due partly to its poor penetration across the blood-brain barrier. Cilengitide, a drug that inhibits avβ3 and avβ5 integrins has shown modest activity in glioblastomas and studies combining it with other agents are in progress.

[0015] The use of viral vectors as gene delivery agents has been proposed for the treatment of malignant gliomas. Such viruses may be engineered to produce anticancer activity by expressing transgenes whose products exert a tumoricidal effect.

[0016] Several of such approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly used approach, but oncolytic conditionally replicating adenoviruses and herpes simplex virus mutant vectors, p53, interleukins, interferons, and antisense oligonucleotides have also been used.

[0017] U.S. Pat. No. 5,747,340 teaches use of a murine endothelial cell-specific promoter which shows selectivity towards angiogenic cells.

[0018] International Application WO/2008/132729 teaches viral vectors comprising endothelial cell specific promoters which directs expression of a transgene in angiogenic cells for the treatment of cancer.

SUMMARY OF THE INVENTION

[0019] According to an aspect of some embodiments of the present invention there is provided a use of a viral vector for preparation of a medicament for the treatment of a malignant glioma, the nucleic acid construct comprising:

[0020] (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c), the first polynucleotide sequence comprising SEQ ID NOs: 2 and 3; and

[0021] (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter.

[0022] According to an aspect of some embodiments of the present invention there is provided a use of a viral vector for the treatment of a malignant glioma, the nucleic acid construct comprising:

[0023] (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c), the first polynucleotide sequence comprising SEQ ID NOs: 2 and 3; and

[0024] (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter.

[0025] According to an aspect of some embodiments of the present invention there is provided a method of treating a malignant glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a viral vector comprising:

[0026] (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c), the first polynucleotide sequence comprising SEQ ID NOs: 2 and 3; and

[0027] (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter, thereby treating the malignant glioma.

[0028] According to some embodiments of the present invention the promoter is set forth in SEQ ID NO: 12.

[0029] According to some embodiments of the present invention the promoter is set forth in SEQ ID NO: 13.

[0030] According to some embodiments of the present invention the viral vector is an adenoviral vector.

[0031] According to some embodiments of the present invention the adenoviral vector is a non-replicating adenoviral vector.

[0032] According to some embodiments of the present invention the promoter comprises at least one copy of a sequence set forth in SEQ ID NO: 6.

[0033] According to some embodiments of the present invention the promoter comprises at least two copies of a sequence set forth in SEQ ID NO: 6.

[0034] According to some embodiments of the present invention the promoter comprises a sequence as set forth in SEQ ID NO: 7.

[0035] According to some embodiments of the present invention the promoter comprises a sequence as set forth in SEQ ID NO: 8.

[0036] According to some embodiments of the present invention the promoter comprises a hypoxia response element (HRE) as set forth in SEQ ID NO: 5.

[0037] According to some embodiments of the present invention the viral vector consists of a sequence as set forth in SEQ ID NO: 9 or SEQ ID NO: 10.

[0038] According to some embodiments of the present invention the malignant glioma is selected from the group consisting of glioblastoma, astrocytoma, oligodendroglioma, and ependymoma, and juvenile pilocystic astrocytoma.

[0039] According to some embodiments of the present invention the therapeutically effective amount of the nucleic acid construct is about 10³ to about 10¹⁶ virus particles.

[0040] According to some embodiments of the present invention the therapeutically effective amount of the nucleic acid construct is about 10⁵ to about 10¹³ virus particles.

[0041] According to some embodiments of the present invention the therapeutically effective amount of the nucleic acid construct is about 10⁷ to about 10¹² virus particles.

[0042] According to some embodiments of the present invention the therapeutically effective amount of the nucleic acid construct is about 1×10¹² to about 5×10¹² virus particles.

[0043] According to some embodiments of the present invention the therapeutically effective amount of the nucleic acid construct is about 1×10¹³ to about 5×10¹³ virus particles.

[0044] According to some embodiments of the present invention the administering comprises intravenous administration.

[0045] According to some embodiments of the present invention the administering comprises local administration.

[0046] According to some embodiments of the present invention the administering is in at least two, or at least three or more doses of said viral vector.

[0047] Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings and images. With specific reference now to the drawings and images in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0049] In the drawings:

[0050] FIG. 1 is a time chart illustrating an exemplary treatment schedule to measure the in-vivo effects of VB-111 in nude rats pre-inoculated with U87 tumor cells.

[0051] FIG. 2 is a graph illustrating the effect of VB-111 on survival of rats pre-inoculated with U87 tumor cells.

[0052] FIG. 3 is a graph illustrating the effect of VB-111 on tumor size (as measured by luciferase activity) of rats pre-inoculated with U87 tumor cells.

[0053] FIG. 4 is a graph illustrating the effect of VB-111 on tumor size (as measured by MRI) of rats pre-inoculated with U87 tumor cells.

[0054] FIGS. 5A-F are photographs of brain slices illustrating the effect of VB-111 on tumor size (as measured by MRI) of rats pre-inoculated with U87 tumor cells.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0055] The present invention, in some embodiments thereof, relates to compositions and methods for treating malignant gliomas and, more particularly, but not exclusively, for treating Glioblastoma multiforme (GBM).

[0056] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0057] Malignant gliomas, the most common subtype of primary brain tumors, are aggressive, highly invasive, and neurologically destructive tumors. These tumors are considered to be among the deadliest of all human cancers. In its most aggressive form, glioblastoma (GBM), median survival ranges from 9 to 12 months. Despite several decades of technological advances in neurosurgery and radiation therapy there has been no significant change in the overall statistics.

[0058] Gene therapy approaches for the treatment of malignant gliomas have been attempted. However, while these approaches have proved successful in vitro and in animal models, these strategies have met with limited success in clinical trials. It is believed that the low in vivo infection efficiency of the vectors is connected to the histological structure of the glioblastomas. These are very solid tumors, which are almost completely impermeable to diffusion of big particles such as viruses.

[0059] The present inventors surprisingly found that treatment of glioblastomas in animals could be carried out effectively using viral vectors encoding a toxic molecule (Fas-chimera (Fas-c)) under the control of a promoter which directs transcription in endothelial cells.

[0060] Using an animal model of glioblastoma whereby rats were pre-inoculated with U87 tumor cells, the present inventors showed that administration of such viral vectors decreased the size of the luciferase-tagged tumors as measured by luciferase activity (FIG. 3) and MRI (FIGS. 4 and 5). The present inventors further showed that administration of such viral vectors increased survival of the rats (FIG. 2).

[0061] Thus, according to one aspect of the present invention, there is provided a method of treating a malignant glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a viral vector comprising:

[0062] (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c); and

[0063] (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter, thereby treating the malignant glioma.

[0064] As used herein, the phrase "malignant glioma" refers to a primary central nervous system tumor typically characterized by over-expression of growth factor receptors and/or tumor associated antigens. According to one embodiment the malignant glioma exhibits epidermal growth factor receptor (EGFR) overexpression. According to one embodiment the malignant glioma exhibits platelet-derived growth factor receptor (PDFR) overexpression. According to another embodiment the malignant glioma exhibits both platelet-derived growth factor receptor (PDFR) overexpression and epidermal growth factor receptor (EGFR) overexpression.

[0065] Examples of malignant gliomas include, but are not limited to glioblastoma, astrocytoma, oligodendroglioma, ependymoma; and juvenile onset neoplasms such as juvenile pilocystic astrocytoma.

[0066] Contemplated subjects to be treated include mammals--e.g. humans. According to one embodiment the subject has received a prior treatment for the malignant glioma (e.g. radiotherapy and/or chemotherapy) and the malignant glioma has relapsed. According to another embodiment, the subject has not received a prior treatment for the malignant glioma.

[0067] The phrase "viral vector" refers to a replication competent or replication-deficient viral particle which are capable of transferring nucleic acid molecules into a host.

[0068] The present inventors contemplate use of Replication Defective Vectors and Replication Defective Vector-Producing Packaging Cells. Examples of such vectors are adenoviral vectors, AAV vectors and retroviral vectors and others described in Shir et al, Cellular and Molecular Neurobiology, Vol. 21, No. 6, December 2001, the contents of which are incorporated herein by reference.

[0069] The term "virus" refers to any of the obligate intracellular parasites having no protein-synthesizing or energy-generating mechanism. The viral genome may be RNA or DNA contained with a coated structure of protein of a lipid membrane. Examples of viruses useful in the practice of the present invention include baculoviridiae, parvoviridiae, picomoviridiae, herepesviridiae, poxyiridiae, adenoviridiae, picotmaviridiae. The term recombinant virus includes chimeric (or even multimeric) viruses, i.e. vectors constructed using complementary coding sequences from more than one viral subtype. (See, e.g. Feng, et al. Nature Biotechnology 15:866-870) The term "adenovirus" is synonymous with the term "adenoviral vector" and refers to viruses of the genus adenoviridiae. The term adenoviridiae refers collectively to animal adenoviruses of the genus mastadenovirus including but no limited to human, bovine, ovine, equine, canine, porcine, murine and simian adenovirus subgenera. In particular, human adenoviruses includes the A-F subgenera as well as the individual serotypes thereof the individual serotypes and A-F subgenera including but not limited to human adenovirus types 1, 2, 3, 4, 4a, 5, 6, 7, 8, 9, 10, 11 (Ad11A and Ad 11P), 12, 13, 14, 15, 16, 17, 18, 19, 19a, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 34a, 35, 35p, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, and 91. The term bovine adenoviruses includes but is not limited to bovine adenovirus types 1, 2, 3, 4, 7, and 10. The term canine adenoviruses includes but is not limited to canine types 1 (strains CLL, Glaxo, RI261, Utrect, Toronto 26-61) and 2. The term equine adenoviruses includes but is not limited to equine types 1 and 2. The term porcine adenoviruses includes but is not limited to porcine types 3 and 4. In one embodiment of the invention, the adenovirus is derived from the human adenovirus serotypes 2 or 5. For purposes of this invention, adenovirus vectors can be replication-competent or replication deficient in a target cell. In some embodiments, the adenovirus vectors are conditionally or selectively replicating adenoviruses, wherein a gene[s] required for viral replication is [are] operatively linked to a cell and/or context-specific promoter. Examples of selectively replicating or conditionally replicating viral vectors are known in the art (see, for example, U.S. Pat. No. 7,691,370). In one embodiment, the adenovirus vector is a conditionally replicating adenovirus wherein the E1 gene is under transcriptional control of the pre-proendothelin promoter PPE-1 (PPE-1, SEQ ID NO: 13). In another embodiment, the adenovirus vector is a conditionally replicating or selectively replicating adenovirus wherein the E1 gene is under transcriptional control of the modified pre-proendothelin promoter PPE-1-3X (PPE-1-3X, SEQ ID NO: 12). In some embodiments, adenovirus vectors suitable for use with the present invention include all adenovirus serotypes having hexon protein structure. Viral vectors suitable for therapeutic use include adenoviral vectors, retrovirusal vectors, AAV, herpesvirus vectors and the like. Engineering and production of viral vectors is well known in the art, as described in detail in, for example, U.S. Pat. No. 7,732,129 or 6,649,158, which are incorporated herein by reference, in their entirety. In specific embodiments, the adenovirus is a C-type adenovirus (Ad5, Ad2), a B-type adenovirus (Ad3, Ad16, Ad21, Ad35, Ad50), an E-type adenovirus (Ad4) or an F-type adenovirus (Ad41).

[0070] As used herein, the phrase adenoviral vector refers to a vector in which, among the nucleic acid molecules in the viral particle, sequences necessary to function as a viral vector are based on the adenoviral genome.

[0071] According to one embodiment the adenoviral vector is a non-replicating serotype 5 (Ad5) adenoviral vector.

[0072] According to another embodiment, the adenoviral vector comprises a sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 11.

[0073] It will be appreciated that the present invention also contemplates use of oncolytic viruses which reproduce themselves in cancer cells and subsequently kill the initially infected cells by lysis. Such viruses proceed to infect adjacent cells thus repeating the cycle. Contemplated example of oncolytic viruses include, but are not limited to Herpes Simplex Virus, conditionally replicative Ads (CRAds) and reoviruses.

[0074] Two major strategies for development of CRAd vectors have been developed, mainly focusing on the genetic engineering of the early 1 (E1) genes to restrict virus replication to target cells and to spare normal tissue. Genetic complementation-type (type 1) CRAds, such as Ad524, have a mutation in the immediately early (E1A) or early (E1B) adenoviral region, which is complemented in tumor cells but not in normal cells. In trans complementation-type (type 2) CRAds, virus replication is controlled via a tumor/tissue-specific promoter.

[0075] Reovirus is a naturally occurring oncolytic virus that requires activated Ras signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases.

[0076] As mentioned the viral vectors of this aspect of the present invention comprise:

[0077] (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c); and

[0078] (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter, thereby treating the malignant glioma.

[0079] Typically, such viral vectors are constructed using genetic recombination technology--i.e. recombinant viral vectors.

[0080] The Fas-chimera (Fas-c), is a previously described fusion of two "death receptors", constructed from the extracellular region of TNFR1 (SEQ ID NO: 2) and the trans-membrane and intracellular regions of Fas (SEQ ID NO: 3) [Boldin M P et al. J Biol Chem (1995) 270(14):7795-8].

[0081] According to one embodiment the Fas-c is encoded by a polynucleotide as set forth in SEQ ID NO: 4.

[0082] It will be appreciated that the present invention also contemplates use of a viral construct (e.g. an adenoviral construct) comprising an endothelial/periendothelial cell-specific promoter operatively linked to other cytotoxic polypeptides for the treatment of malignant glioma.

[0083] Such polypeptides, include but are not limited to suicide polypeptides such as p53 and egr-1-TNF-alpha, cytotoxic pro-drug/enzymes for drug susceptibility therapy such as ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase, and antimetastatic polypeptides such as 5 E1A.

[0084] The term "promoter" as used herein refers to a DNA sequence which directs transcription of a polynucleotide sequence operatively linked thereto in the cell in a constitutive or inducible manner. The promoter may also comprise enhancer elements which stimulate transcription from the linked promoter.

[0085] As used herein, the phrase endothelial cell-specific promoter refers to a promoter which directs expression of a gene operatively linked thereto in endothelial cells, wherein the level of expression in endothelial cells is at least 2 times higher than in non-endothelial cells. According to a particular embodiment, the level of expression in endothelial cells is at least 5 times higher than in non-endothelial cells.

[0086] As used herein, the phrase periendothelial cell-specific promoter refers to a promoter which directs expression of a gene operatively linked thereto in periendothelial cells (i.e., pericytes in small vessels or smooth muscle cells in larger vessels), wherein the level of expression in endothelial cells is at least 2 times higher than in non-periendothelial cells. According to a particular embodiment, the level of expression in periendothelial cells is at least 5 times higher than in non-periendothelial cells.

[0087] Exemplary endothelial cell-specific promoters or periendothelial cell-specific promoters include, but are not limited to the preproendothelin-1 (PPE-1) promoter, and modifications thereof such as described herein below, the TIE-1 promoter, the TIE-2 promoter, the Endoglin promoter, the von Willerband promoter, the KDR/flk-1 promoter, The FLT-1 promoter, the Egr-1 promoter, the ICAM-1 promoter, the VCAM-1 promoter, the PECAM-1 promoter and the aortic carboxypeptidase-like protein (ACLP) promoter.

[0088] The preproendothelial promoter refers to the preproendothelin-1 promoter, of mammalian origin. In one embodiment, the preproendothelin 1 promoter is a murine preproendothelin 1 promoter as set forth in SEQ ID NO: 13.

[0089] According to one embodiment the promoter comprises at least one copy of an enhancer element that confers endothelial cell specific transcriptional activity. According to one embodiment the enhancer element is naturally found positioned between the -364 bp and -320 bp of the murine PPE-1 promoter (as set forth in SEQ ID NO: 6). Preferably, the promoter comprises at least two and more preferably three of the above described enhancer elements. According to a specific embodiment, the promoter comprises two of the above described enhancer elements on one strand of the promoter DNA and one of the above described enhancer element on the complementary strand of the promoter DNA (as set forth in SEQ ID NO:7).

[0090] According to another embodiment, the promoter further comprises at least one hypoxia response element--e.g. comprising a sequence as set forth in SEQ ID NO: 5.

[0091] An exemplary promoter which can be used in the context of the present invention comprises a sequence as set forth in SEQ ID NO: 12. This promoter is also referred to herein as the PPE-1-3x promoter. This sequence comprises SEQ ID NO: 5 and SEQ ID NO: 7 (which itself comprises two copies of SEQ ID NO: 6 either side of one copy of SEQ ID NO: 8).

[0092] According to a particular embodiment of this aspect of the present invention, the viral vector consists of a sequence as set forth in SEQ ID NOs: 9 or 10. This viral vector is also referred to herein as VB111 and AD5PPE-1-3X-fas-chimera.

[0093] This sequence comprises SEQ ID NO: 12 in the antisense orientation at position 460-1437.

[0094] This sequence also comprises SEQ ID NO: 7 in the antisense orientation at position 894-1036; a single copy of SEQ ID NO: 8 in the antisense orientation at position 951-997; a first copy of SEQ ID NO: 6 in the antisense orientation at position 907-950; a second copy of SEQ ID NO: 6 in the antisense orientation at position 993-1036; and a third copy of SEQ ID NO: 6 at position 823-866 in the sense orientation.

[0095] In some embodiments of the invention, the viral vector comprises additional polynucleotide sequences capable of enhancing or inhibiting transcriptional activity of an endothelial specific promoter. According to an aspect of some embodiments of the invention, the additional polynucleotide sequence includes an isolated polynucleotide comprising at least 6 nucleotides of element X of a pre-proendothelin (PPE-1) promoter, the element X having a wild type sequence as set forth by SEQ ID NO:6, wherein the at least 6 nucleotides comprise at least 2 consecutive sequences derived from SEQ ID NO:6, each of the at least 2 consecutive sequences comprises at least 3 nucleotides, at least one of the at least 3 nucleotide being positioned next to at least one nucleotide position in SEQ ID NO:6, the at least one nucleotide position in SEQ ID NO:6 is selected from the group consisting of:

[0096] (i) at least one nucleotide of wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC);

[0097] (ii) at least one nucleotide of wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG);

[0098] (iii) at least one nucleotide of wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC);

[0099] (iv) at least one nucleotide of wild type M6 sequence set forth by SEQ ID NO: 17 (GGGTG);

[0100] (v) at least one nucleotide of wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT);

[0101] (vi) at least one nucleotide of wild type M1 sequence set forth by SEQ ID NO: 20 (GTACT); and

[0102] (v) at least one nucleotide of wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT);

[0103] wherein the at least one nucleotide position is mutated as compared to SEQ ID NO:6 by at least one nucleotide substitution, at least one nucleotide deletion and/or at least one nucleotide insertion, with the proviso that a mutation of the at least one nucleotide position does not result in nucleotides GGTA at position 21-24 of SEQ ID NO:6 and/or in nucleotides CATG at position 29-32 of SEQ ID NO:6, such that when the isolated polynucleotide is integrated into the PPE-1 promoter and placed upstream of a reporter gene (e.g., luciferase coding sequence) the expression level of the reporter gene is upregulated or downregulated as compared to when SEQ ID NO:6 is similarly integrated into the PPE-1 promoter and placed upstream of the reporter gene coding sequence.

[0104] According to some embodiments of the invention, the isolated polynucleotide is not naturally occurring in a genome or a whole chromosome sequence of an organism.

[0105] As used herein the phrase "naturally occurring" refers to as found in nature, without any man-made modifications.

[0106] As described above, the at least 6 nucleotides of element X comprise at least 2 consecutive sequences derived from SEQ ID NO:6.

[0107] As used herein the phrase "consecutive sequence derived from SEQ ID NO:6" refers to a nucleic acid sequence (a polynucleotide) in which the nucleotides appear in the same order as in the nucleic acid sequence of SEQ ID NO:6 from which they are derived. It should be noted that the order of nucleotides is determined by the chemical bond (phosphodiester bond) formed between a 3'-OH of a preceding nucleotide and the 5'-phosphate of the following nucleotide.

[0108] According to some embodiments of the invention, each of the at least 2 consecutive sequences comprises at least 3 nucleotides, e.g., 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotide, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, 40 nucleotides, 41 nucleotides of SEQ ID NO:6.

[0109] As described, the isolated polynucleotide comprises at least 2 consecutive sequences derived from SEQ ID NO:6. According to some embodiments of the invention, the isolated polynucleotide comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 consecutive sequences derived from SEQ ID NO:6.

[0110] As used herein the phrase "wild type" with respect to a nucleotide sequence refers to the nucleic acid sequence as appears in SEQ ID NO:6. Examples include, but are not limited to wild type M4 sequence (SEQ ID NO: 15), wild type M5 sequence (SEQ ID NO: 16), wild type M8 (SEQ ID NO:19), wild type M6 sequence (SEQ ID NO:17), wild type M7 sequence (SEQ ID NO:18), wild type M1 (SEQ ID NO:20) and wild type M3 sequence (SEQ ID NO:21).

[0111] According to some embodiments of the invention, the mutation is an insertion of at least one nucleotide in a nucleotide position with respect to SEQ ID NO:6. According to some embodiments of the invention, the insertion includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 nucleotides, e.g., 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 100, at least about 200, at least about 300, or more nucleotides.

[0112] It should be noted that the sequence which is inserted by the mutation can be derived from any source (e.g., species, tissue or cell type), and is not limited to the source of the sequence of element X.

[0113] According to some embodiments of the invention, the mutation is a combination of any of the mutation types described above, i.e., substitution, insertion and deletion. For example, while one nucleotide position in SEQ ID NO:6 can be subject to a substitution mutation, another nucleotide position in SEQ ID NO:6 can be subject to a deletion or insertion. Additionally or alternatively, while one nucleotide position in SEQ ID NO:6 can be subject to a deletion mutation, another nucleotide position in SEQ ID NO:6 can be subject to a substitution or insertion. Additionally or alternatively, while one nucleotide position in SEQ ID NO:6 can be subject to an insertion mutation, another nucleotide position in SEQ ID NO:6 can be subject to a substitution or deletion. It should be noted that various other combinations are possible.

[0114] According to specific embodiments of the invention, the mutation in the isolated polynucleotide of the invention does not result in nucleotides GGTA at position 21-24 of SEQ ID NO:6 and/or in nucleotides CATG at position 29-32 of SEQ ID NO:6.

[0115] As used herein the phrase "integrated into the PPE-1 promoter" refers to a nucleotide sequence (the isolated polynucleotide) which is covalently conjugated within the PPE-1 promoter sequence.

[0116] According to some embodiments of the invention, the isolated polynucleotide further comprises at least one copy of a nucleic acid sequence selected from the group consisting of:

[0117] (i) wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC),

[0118] (ii) wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG),

[0119] (iii) wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC),

[0120] (iv) wild type M6 sequence set forth by SEQ ID NO: 17 (GGGTG),

[0121] (v) wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT);

[0122] (vi) wild type M1 sequence set forth by SEQ ID NO: 20 (GTACT), and

[0123] (vii) wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT).

[0124] According to some embodiments of the invention, the isolated polynucleotide is integrated into (within), downstream of, or upstream of any known (or unknown) promoter sequence to thereby regulate (e.g., increase, decrease, modulate tissue-specificity, modulate inductive or constitutive expression) the transcriptional promoting activity of the promoter.

[0125] According to some embodiments of the invention, the isolated polynucleotide is for increasing expression of a heterologous polynucleotide operably linked thereto in endothelial cells. Such a polynucleotide can include wild type sequences of M4 and/or M5 in the presence or absence of additional sequences from element X, and/or in the presence of other mutated sequences from element X.

[0126] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC).

[0127] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG).

[0128] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and at least one copy of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG).

[0129] According to some embodiments of the invention, the at least one nucleotide position which is mutated as compared to SEQ ID NO:6 is at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC). It should be noted that such an isolated polynucleotide may further include a wild type M6 sequence (SEQ ID NO:17) and/or a wild type M7 sequence (SEQ ID NO:18)

[0130] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and a mutation in at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:55-62.

[0131] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and a mutation in at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs: 63-66.

[0132] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and a mutation in at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs: 67-70.

[0133] According to some embodiments of the invention, the isolated polynucleotide further comprising at least one copy of wild type M1 sequence set forth by SEQ ID NO: (GTACT).

[0134] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M1 sequence set forth by SEQ ID NO: 20 (GTACT), and a mutation in at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs: 71-105.

[0135] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M1 sequence set forth by SEQ ID NO: 20 (GTACT) and a mutation in at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs: 106-136.

[0136] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M1 sequence set forth by SEQ ID NO: 20 (GTACT) and a mutation in at least one nucleotide of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:137-152.

[0137] According to some embodiments of the invention, the isolated polynucleotide reduces expression of a heterologous polynucleotide operably linked thereto in endothelial cells. Such a polynucleotide can include mutations in M4 and/or M5 in the presence or absence of additional sequences from element X, and/or in the presence of other mutated sequences from element X.

[0138] According to some embodiments of the invention, the at least one nucleotide position which is mutated as compared to SEQ ID NO:6 is at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC).

[0139] Non-limiting examples of isolated polynucleotides which includes a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO:46 (CATTC) are provided in SEQ ID NOs:153-162.

[0140] According to some embodiments of the invention, the at least one nucleotide position which is mutated as compared to SEQ ID NO:6 is at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG).

[0141] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) are provided in SEQ ID NOs:163-171.

[0142] According to some embodiments of the invention, the at least one nucleotide position which is mutated as compared to SEQ ID NO:6 is at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG).

[0143] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) are provided in SEQ ID NOs:172-180.

[0144] According to some embodiments of the invention, the isolated polynucleotide is for increasing expression of a heterologous polynucleotide operably linked thereto in cells other than endothelial cells. Such a polynucleotide can include mutations in M4 and/or M5 and wild type sequences of M6 and/or M7, in the presence or absence of additional sequences from element X, and/or in the presence of other mutated sequences from element X.

[0145] According to some embodiments of the invention, the isolated polynucleotide comprises a mutation in M4 (SEQ ID NO: 15) and/or in M5 (SEQ ID NO: 16) and at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and/or at least one copy of wild type M7 set forth by SEQ ID NO:18.

[0146] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) are provided in SEQ ID NOs:181-182.

[0147] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) are provided in SEQ ID NOs:183-189.

[0148] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) are provided in SEQ ID NOs:190-191.

[0149] According to some embodiments of the invention, the isolated polynucleotide further comprises at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT).

[0150] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:192-195.

[0151] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:196-198.

[0152] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:199-202.

[0153] According to some embodiments of the invention, the isolated polynucleotide further comprises at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT).

[0154] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one, copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:203-205.

[0155] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:206-207.

[0156] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:208-209.

[0157] According to some embodiments of the invention, the isolated polynucleotide reduces expression in cells of a heterologous polynucleotide operably linked thereto. Such a polynucleotide can include mutations in M4, M5, M6 and/or M7, in the presence or absence of additional sequences from element X, and/or in the presence of other mutated sequences from element X.

[0158] According to some embodiments of the invention, the isolated polynucleotide comprises at least one mutation in wild type M4 (SEQ ID NO: 15) and/or in wild type M5 (SEQ ID NO:47) and in wild type M6 set forth by SEQ ID NO: 17 (GGGTG).

[0159] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) are provided in SEQ ID NOs:210-213.

[0160] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) are provided in SEQ ID NOs:214-222.

[0161] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), and a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) are provided in SEQ ID NOs:223-231.

[0162] According to some embodiments of the invention, the isolated polynucleotide further comprises at least one mutation in wild type M7 set forth by SEQ ID NO: 18 (ACTTT).

[0163] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:232-236.

[0164] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:237-240.

[0165] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), and a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:241-248.

[0166] According to some embodiments of the invention, the isolated polynucleotide further comprises at least one mutation in wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one mutation in wild type M7 set forth by SEQ ID NO: 18 (ACTTT).

[0167] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:249-258.

[0168] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:259-264.

[0169] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) are provided in SEQ ID NOs:265-270.

[0170] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) with additional wild type or mutated sequences derived from element X (SEQ ID NO:6).

[0171] Non-limiting examples of isolated polynucleotides which includes a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:271-279.

[0172] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:280-287.

[0173] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:288-291.

[0174] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:294-298.

[0175] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:299-301.

[0176] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:302-303.

[0177] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:304-308.

[0178] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:309-311.

[0179] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:312-315.

[0180] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NO:316.

[0181] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NO:317.

[0182] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NO:318.

[0183] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:319-327.

[0184] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:328-333.

[0185] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:334-337.

[0186] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:338-344.

[0187] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:345-348.

[0188] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:349-354.

[0189] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:355-361.

[0190] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:362-365.

[0191] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) are provided in SEQ ID NOs:366-369.

[0192] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) with additional wild type or mutated sequences derived from element X (SEQ ID NO:6).

[0193] Non-limiting examples of isolated polynucleotides which includes a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:378-384.

[0194] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:628-634.

[0195] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:370-377.

[0196] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:385-390.

[0197] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:391-396.

[0198] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:397-401.

[0199] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACM) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:402-409.

[0200] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACM) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:410-417.

[0201] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:418-423.

[0202] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:424-425.

[0203] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:538-540.

[0204] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NO:426.

[0205] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:427-435.

[0206] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:436-444.

[0207] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:445-451.

[0208] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:452-458.

[0209] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:459-465.

[0210] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NO:466.

[0211] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:467-471.

[0212] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:472-477.

[0213] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:478-483.

[0214] According to some embodiments of the invention, the isolated polynucleotide further comprises at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) with additional wild type or mutated sequences derived from element X (SEQ ID NO:6).

[0215] Non-limiting examples of isolated polynucleotides which includes a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:484-495.

[0216] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:496-507.

[0217] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:508-515.

[0218] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:516-519.

[0219] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:520-523.

[0220] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:524-525.

[0221] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:526-529.

[0222] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:530-533.

[0223] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:534-535.

[0224] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ NO: 21 (CTTTT) are provided in SEQ ID NOs:536-537.

[0225] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT) at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:538-539.

[0226] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), at least one copy of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG); at least one copy of the wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NO:540.

[0227] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:541-547.

[0228] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:548-554.

[0229] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), at least one copy of the wild type M8 to sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:555-559.

[0230] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:560-566.

[0231] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:567-573.

[0232] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:574-578.

[0233] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:579-583.

[0234] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:584-588.

[0235] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of the wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC), a mutation in at least one nucleotide of the wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG), a mutation in at least one nucleotide position of the wild type M6 set forth by SEQ ID NO: 17 (GGGTG), a mutation in at least one nucleotide position of the wild type M7 set forth by SEQ ID NO: 18 (ACTTT), at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) are provided in SEQ ID NOs:589-592.

[0236] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of wild type M3 sequence (SEQ ID NO: 21) and at least one copy of wild type M8 sequence (SEQ ID NO: 19), with at least one mutation in wild type M6 (SEQ ID NO: 17) and/or in wild type M7 (SEQ ID NO:50).

[0237] Non-limiting examples of isolated polynucleotides which include at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), with a mutation in at least one nucleotide of the wild type M6 sequence (SEQ ID NO: 17), and/or a mutation in at least one nucleotide of the wild type M7 (SEQ ID NO: 18) are provided in SEQ ID NOs:593-600.

[0238] The present inventors have envisaged that an isolated polynucleotide which includes the wild type M8 sequence (SEQ ID NO: 19) and/or the wild type M3 (SEQ ID NO: 21) sequence in addition to tissue specific enhancers (e.g., wild type M4 and/or wild type M5), and/or induced enhancers (e.g., developmentally related- or stress related-enhancers) is expected to exert a more specific regulatory effect by suppressing expression in non-target cells or under non-induced conditions.

[0239] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and an endothelial specific enhancer sequence.

[0240] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of wild type M4 sequence set forth by SEQ ID NO: 15.

[0241] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of wild type M5 sequence set forth by SEQ ID NO:16.

[0242] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC), at least one copy of wild type M4 sequence set forth by SEQ ID NO: 15 and at least one copy of wild type M5 sequence set forth by SEQ ID NO:16.

[0243] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) and an endothelial specific enhancer sequence.

[0244] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) and at least one copy of wild type M4 sequence set forth by SEQ ID NO: 15.

[0245] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT) and at least one copy of wild type M5 sequence set forth by SEQ ID NO:16.

[0246] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), at least one copy of wild type M4 sequence set forth by SEQ ID NO: 15 and at least one copy of wild type M5 sequence set forth by SEQ ID NO:16.

[0247] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), at least one copy of wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and an endothelial specific enhancer sequence.

[0248] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), at least one copy of wild type M8 sequence set forth by SEQ ID. NO: 19 (GCTTC) and at least one copy of wild type M4 sequence set forth by SEQ ID NO: 15.

[0249] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), at least one copy of wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one copy of wild type M5 sequence set forth by SEQ ID NO: 16.

[0250] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), at least one copy of wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC), at least one copy of wild type M4 sequence set forth by SEQ ID NO: 15 and at least one copy of wild type M5 sequence set forth by SEQ ID NO: 16.

[0251] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of the wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT), at least one copy of wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC) and at least one enhancer element such as wild type M6 (SEQ ID NO: 17) and/or wild type M7 sequence (SEQ ID NO:18).

[0252] According to some embodiments of the invention, the isolated polynucleotide includes at least one copy of wild type M8 with additional flanking sequences such as at least one copy of a wild type M8 sequence (SEQ ID NO:19), at least one copy of wild type M7 (SEQ ID NO: 18) and/or wild type M9 sequence (SEQ ID NO: 14, CTGGA); and/or the isolated polynucleotide includes at least one copy of wild type M8 and at least one mutation in M7, with or without M9 (SEQ ID NO: 22). Such polynucleotides can be used as a non-specific repressor.

[0253] According to some embodiments of the invention, the isolated polynucleotide is for increasing expression of a heterologous polynucleotide operably linked thereto in cells/tissues.

[0254] According to some embodiments of the invention, the isolated polynucleotide comprises at least one copy of wild type M6 sequence set forth by SEQ ID NO: 17 (GGGTG) and/or at least one copy of wild type. M7 sequence set forth by SEQ ID NO: 18 (ACTTT).

[0255] According to some embodiments of the invention, the isolated polynucleotide includes at least one copy of wild type M6 (SEQ ID NO: 17) and a mutation in at least one nucleotide of wild type M8 (SEQ ID NO: 19).

[0256] Non-limiting examples of isolated polynucleotide which include at least one copy of wild type M6 (SEQ ID NO: 17) and a mutation in at least one nucleotide of the wild type M8 (SEQ ID NO: 19) are provided in SEQ ID NOs:23-26.

[0257] According to some embodiments of the invention, the isolated polynucleotide includes at least one copy of wild type M7 (SEQ ID NO: 18) and a mutation in at least one nucleotide of wild type M8 (SEQ ID NO: 19).

[0258] Non-limiting examples of isolated polynucleotide which include at least one copy of wild type M7 (SEQ ID NO: 18) and a mutation in at least one nucleotide of the wild type M8 (SEQ ID NO: 19) are provided in SEQ ID NOs:27-28.

[0259] According to some embodiments of the invention, the isolated polynucleotide includes at least one copy of wild type M6 (SEQ ID NO: 17), at least one copy of wild type M7 (SEQ ID NO: 18) and a mutation in at least one nucleotide of wild type M8 (SEQ ID NO: 19).

[0260] According to some embodiments of the invention, the isolated polynucleotide includes at least one copy of wild type M1 (SEQ ID NO: 20) and a mutation in at least one nucleotide of wild type M8 (SEQ ID NO: 19).

[0261] Non-limiting examples of isolated polynucleotide which include at least one copy of wild type M1 (SEQ ID NO: 20) and a mutation in at least one nucleotide of the wild type M8 (SEQ ID NO: 19) are provided in SEQ ID NOs:43-54 and 601-632.

[0262] According to some embodiments of the invention, the isolated polynucleotide includes at least one copy of wild type M1 (SEQ ID NO: 20), at least one copy of wild type M6 (SEQ ID NO: 17) and/or at least one copy of wild type M7 (SEQ ID NO: 18) and a mutation in at least one nucleotide of wild type M8 (SEQ ID NO: 19).

[0263] Non-limiting examples of isolated polynucleotides which include a mutation in at least one nucleotide of wild type M8 (SEQ ID NO: 19) and at least one copy of wild type M1 (SEQ ID NO: 20), wild type M6 (SEQ ID NO: 17) and/or wild type M7 (SEQ ID NO: 18) are provided in SEQ ID NOs:29-42.

[0264] Additional examples of regulatory isolated polynucleotides which can be used according to some embodiments of the invention are provided (SEQ ID NOs: 633-644) in the Examples section which follows.

[0265] According to an aspect of some embodiments of the invention, there is provided an isolated polynucleotide comprising a nucleic acid sequence which comprises a first polynucleotide comprising the pre-proendothelin (PPE-1) promoter set forth by SEQ ID NO:13 and a second polynucleotide comprising at least one copy of a nucleic acid sequence selected from the group consisting of:

[0266] (i) wild type M4 sequence set forth by SEQ ID NO: 15 (CATTC),

[0267] (ii) wild type M5 sequence set forth by SEQ ID NO: 16 (CAATG),

[0268] (iii) wild type M8 sequence set forth by SEQ ID NO: 19 (GCTTC),

[0269] (iv) wild type M6 sequence set forth by SEQ ID NO: 17 (GGGTG),

[0270] (v) wild type M7 sequence set forth by SEQ ID NO: 18 (ACTTT);

[0271] (vi) wild type M1 sequence set forth by SEQ ID NO: 20 (GTACT), and

[0272] (vii) wild type M3 sequence set forth by SEQ ID NO: 21 (CTTTT);

[0273] with the proviso that the second polynucleotide is not SEQ ID NO:6 (element X), and wherein the isolated polynucleotide is not SEQ ID NO:12 (PPE-1-3X).

[0274] According to some embodiments of the invention, each of the wild type M4, M5, M8, M6, M7 and/or M1 sequences is placed in a head to tail (5'→3') orientation with respect to the PPE-1 promoter set forth by SEQ ID NO:13.

[0275] According to some embodiments of the invention, each of the wild type M4, M5, M8, M6, M7 and/or M1 sequences is placed in a tail to head (3'→5') orientation with respect to the PPE-1 promoter set forth by SEQ ID NO:13.

[0276] According to some embodiments of the invention, the wild type M4, M5, M8, M6, M7 and/or M1 sequences are placed in various orientations (head to tail or tail to head) and/or sequential order with respect the other wild type M4, M5, M8, M6, M7 and/or M1 sequences, and/or with respect to the orientation of SEQ ID NO:13.

[0277] Construction of such viral vectors may be effected using known molecular biology techniques such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Springs Harbor Laboratory, New York (1989, 1992), in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989), Chang et al., Somatic Gene Therapy, CRC Press, Ann Arbor, Mich. (1995), Vega et al., Gene Targeting, CRC Press, Ann Arbor Mich. (1995), Vectors: A Survey of Molecular Cloning Vectors and Their Uses, Butterworths, Boston Mass. (1988) and Gilboa et at. [Biotechniques 4 (6): 504-512, 1986].

[0278] Construction of the viral vector of SEQ ID NO: 9 is described in International Application WO/2008/132729, the contents of which are incorporated herein by reference.

[0279] The viral vector of this aspect of the present invention may be administered per se or as part of a pharmaceutical composition which also includes a physiologically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism.

[0280] As used herein a "pharmaceutical composition" refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0281] Herein the term "active ingredient" refers to the viral vector of the present invention accountable for the biological effect.

[0282] Hereinafter, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases.

[0283] Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0284] Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition, which is incorporated herein by reference.

[0285] Suitable routes of administration may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intracardiac, e.g., into the right or left ventricular cavity, into the common coronary artery, intravenous, inrtaperitoneal, intranasal, or intraocular injections. Injection of the viral vectors into a spinal fluid can also be used as a mode of administration.

[0286] In order to enhance delivery of the virus to the central nervous system (CNS) various approaches may be taken. These include: neurosurgical strategies (e.g., intracerebral injection or intracerebroventricular infusion) and molecular manipulation of the virus. Thus for example, Tang et al., Gene Therapy (2007) 14, 523-532 teaches re-directing Ad5 vectors to the MTf transcytosis pathway in order to cross the BBB by manipulating the virus to express a full-length melanotransferrin (sCAR-MTf) polypeptide.

[0287] Other approaches for enhancing the delivery of the virus to the CNS include pharmacological strategies designed to increase the lipid solubility of an agent (e.g., conjugation of water-soluble agents to lipid or cholesterol carriers); and the transitory disruption of the integrity of the BBB by hyperosmotic disruption (resulting from the infusion of a mannitol solution into the carotid artery or the use of a biologically active agent such as an angiotensin peptide).

[0288] The present invention also contemplates engineering of the viral vectors in order to avoid, suppress or manipulate the immune response, ideally resulting in sustained expression and immune tolerance to the transgene product--such methods are described for example in Nayak et al., Gene Therapy (12 Nov. 2009), incorporated herein by reference.

[0289] Alternately, one may administer the pharmaceutical composition in a local rather than systemic manner, for example, via injection of the pharmaceutical composition directly into the brain of a patient and even more directly into the tumor cells themselves.

[0290] Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0291] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0292] For injection, the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0293] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0294] For administration by nasal inhalation, the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0295] The pharmaceutical composition described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0296] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.

[0297] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.

[0298] The pharmaceutical composition of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

[0299] Pharmaceutical compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients (i.e. viral particles) effective to prevent, alleviate or ameliorate symptoms of a disorder (e.g., glioblastoma) or prolong the survival of the subject being treated.

[0300] Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0301] For any preparation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays. For example, a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.

[0302] Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).

[0303] Dosage amount and interval may be adjusted individually to provide brain levels of the active ingredient are sufficient to induce or suppress the biological effect (minimal effective concentration, MEC). The MEC will vary for each preparation, but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. Detection assays can be used to determine plasma concentrations.

[0304] Depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.

[0305] The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0306] The therapeutically effective amount of the active ingredient can be formulated in a unit dose. As used herein "unit dose" refers to a physically discrete unit containing a predetermined quantity of an active material calculated to individually or collectively produce a desired effect such as an anti-cancer effect. A single unit dose or a plurality of unit doses can be used to provide the desired effect, such as an anti-cancer therapeutic effect.

[0307] According to one embodiment, about 10³ to about 10¹⁶ virus particles are administered to the subject.

[0308] According to another embodiment, about 10⁵ to about 10¹³ virus particles are administered to the subject.

[0309] According to one embodiment, about 10⁷ to about 10¹² virus particles are administered to the subject.

[0310] According to one embodiment, about 1×10¹² to about 5×10¹² virus particles are administered to the subject.

[0311] According to one embodiment, about 1×10¹³ to about 5×10¹³ virus particles are administered to the subject.

[0312] According to yet another embodiment the subject is administered intravenously with 1×10¹²-1×10¹³ viral particles of SEQ ID NO: 9. or SEQ ID NO: 10.

[0313] According to yet another embodiment the subject is administered intravenously with at least two doses of 1×10¹²-1×10¹³ viral particles of SEQ ID NO: 9. or SEQ ID NO: 10. According to yet another embodiment the subject is administered intravenously with at least three or more doses of 1×10¹²-1×10¹³ viral particles of SEQ ID NO: 9. or SEQ ID NO: 10. In a particular embodiment, the at least two doses are administered at least about 1 day, at least about 3 days, at least about 5 days, at least about 7 days, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 1.25 years, at least about 1.5 years, at least about 1.75 years, at least about 2 years, at least about 2.5 years, at least about 3 years or more apart.

[0314] Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as is further detailed above.

[0315] The vectors of the present invention may be administered with additional ingredients which may improve the uptake of the nucleic acid construct by the cells, expression of the chimeric polypeptide by the nucleic acid construct in the cells, or the activity of the expressed chimeric polypeptide.

[0316] For example, the uptake of adenoviral vectors into EC cells can be enhanced by treating the vectors with engineered antibodies or small peptides. Such "adenobody" treatment, was shown effective in directing adenovirus constructs to EGF receptors on cells (Watkins et at 1997, Gene Therapy 4:1004-1012). In addition, Nicklin et at have shown that a small peptide, isolated via phage display, increased specificity and efficiency of vectors in endothelial cells and decreased the expression in liver cells in culture (Nicklin et at 2000, Circulation 102:231-237). In a recent study, an FGF retargeted adenoviral vector reduced the toxicity of tk in mice (Printz et al 2000, Human Gene Therapy 11:191-204).

[0317] Low dose radiation has been shown to cause breaks in DNA strands primarily in the G2/M phase, cell membrane damage enhancing the bystander effect, and thus may potentiate other cytotoxic and anti-neoplastic therapies, when administered in combination. Vascular endothelial cells may be particularly suitable to such combination, or adjunct, therapies, since it has been demonstrated that low dose radiation specifically targets the apoptotic system of the microvascular endothelial cells (Kolesnick et al., Oncogene 2003; 22:5897-906). Angiostatin has been shown to potentiate the therapeutic effects of low dose radiation (Gorski et al. Can Res 1998; 58:5686-89). However, the effects of radiation are still poorly understood, since irradiation has also been shown to increase pro-angiogenic "tissue repair factors" (Itasaka et al., Am Assoc Canc Res, 2003; abstract 115). Similarly, certain chemotherapeutic agents have been shown to activate specific cytotoxic and apoptotic pathways [doxorubicin, cisplatin and mitomycin C induce accumulation of Fas receptor, FADD, and other proapoptotic signals in the FADD/MORT-1 pathway (Micheau et al., BBRC 1999 256:603-07)].

[0318] For example International Application WO/2008/132729 teaches combined doxorubicin and AdPPE-1 (3x)-Fas-c chimera construct administration in endothelial cells (BAEC). Thus, the viral vectors and the pharmaceutical compositions comprising same of the present invention can be used to treat malignant gliomas alone or in combination with one or more other established or experimental therapeutic regimen for such disorders. Therapeutic regimen for treatment of malignant gliomas suitable for combination with the viral vectors of the present invention include, but are not limited to chemotherapy, radiotherapy, phototherapy and photodynamic therapy, surgery, nutritional therapy, ablative therapy, combined radiotherapy and chemotherapy, brachiotherapy, proton beam therapy, immunotherapy, cellular therapy and photon beam radiosurgical therapy.

[0319] Anti-cancer drugs that can be co-administered with the compounds of the invention include, but are not limited to Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adriamycin; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talisomycin; Taxol; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofuirin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Temozolomide (Temodar®); Bevacizumab, Dorafinib, Sorafenib (Nexavar®), Sunitinib (Sutent®), Vandetanib (ZD6474; Zactima®), Pazopanib (GW786034), and Vatalanib (PTK787), Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride. Additional antineoplastic agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner), and the introduction thereto, 1202-1263, of Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division).

[0320] The viral vectors of the present invention may also be administered with an agent that enhances expression of transgenes in adenoviral-mediated transient expression. For example International Application WO/2008/132729 teaches administration of a corticosteroid (e.g. dexamethasone and/or N-Acetyl Cysteine (NAC) prior to AdPPE-1 (3x)-Fas-c chimera construct administration.

[0321] In addition, the viral vectors of the present invention may also be administered with an agent that brings about transient immunosuppression, such as for example deoxyspergualin (DSG) or cyclophosphamide (see for example Smith et al., Gene Ther. 1996 June; 3(6):496-502) in order to allow for repetitive dosing.

[0322] It is expected that during the life of a patent maturing from this application many relevant chemotherapeutic agents will be developed and the scope of the term chemotherapeutic agent is intended to include all such new technologies a priori.

[0323] As used herein the term "about" refers to ±10%.

[0324] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

[0325] The term "consisting of means "including and limited to".

[0326] The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0327] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0328] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0329] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0330] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0331] As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0332] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0333] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

[0334] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

[0335] Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical, microbiological and recombinant DNA techniques. Such techniques are thoroughly explained in the literature. See, for example, "Molecular Cloning: A laboratory Manual" Sambrook et al., (1989); "Current Protocols in Molecular Biology" Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., "Current Protocols in Molecular Biology", John Wiley and Sons, Baltimore, Md. (1989); Perbal, "A Practical Guide to Molecular Cloning", John Wiley & Sons, New York (1988); Watson et al., "Recombinant DNA", Scientific American Books, New York; Birren et al. (eds) "Genome Analysis: A Laboratory Manual Series", Vols. 1-4, Cold Spring Harbor Laboratory Press, New York (1998); methodologies as set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057; "Cell Biology: A Laboratory Handbook", Volumes I-III Cellis, J. E., ed. (1994); "Culture of Animal Cells--A Manual of Basic Technique" by Freshney, Wiley-Liss, N.Y. (1994), Third Edition; "Current Protocols in Immunology" Volumes Coligan J. E., ed. (1994); Stites et al. (eds), "Basic and Clinical Immunology" (8th Edition), Appleton & Lange, Norwalk, Conn. (1994); Mishell and Shiigi (eds), "Selected Methods in Cellular Immunology", W. H. Freeman and Co., New York (1980); available immunoassays are extensively described in the patent and scientific literature, see, for example, U.S. Pat. Nos. 3,791,932; 3,839,153; 3,850,752; 3,850,578; 3,853,987; 3,867,517; 3,879,262; 3,901,654; 3,935,074; 3,984,533; 3,996,345; 4,034,074; 4,098,876; 4,879,219; 5,011,771 and 5,281,521; "Oligonucleotide Synthesis" Gait, M. J., ed. (1984); "Nucleic Acid Hybridization" Hames, B. D., and Higgins S. J., eds. (1985); "Transcription and Translation" Hames, B. D., and Higgins S. J., eds. (1984); "Animal Cell Culture" Freshney, R. I., ed. (1986); "Immobilized Cells and Enzymes" IRL Press, (1986); "A Practical Guide to Molecular Cloning" Perbal, B., (1984) and "Methods in Enzymology" Vol. 1-317, Academic Press; "PCR Protocols: A Guide To Methods And Applications", Academic Press, San Diego, Calif. (1990); Marshak et al., "Strategies for Protein Purification and Characterization--A Laboratory Course Manual" CSHL Press (1996); all of which are incorporated by reference as if fully set forth herein. Other general references are provided throughout this document. The procedures therein are believed to be well known in the art and are provided for the convenience of the reader. All the information contained therein is incorporated herein by reference.

Example 1

Effect of VB-111 in an Animal Model of Glioblastoma

[0336] Materials and Methods

[0337] Construction and Cloning of the Viral Vector:

[0338] The vector was constructed using a backbone containing most of the genome of adenovirus type 5, as well as partial homology to an adaptor plasmid, which enables recombination.

[0339] The E1 early transcriptional unit was deleted from the backbone plasmid, and further modified by deleting the pWE25 and the Amp resistance selection marker site.

[0340] The adaptor plasmid, containing sequences of the Ad5, CMV promoter, MCS, and SV40 polyA was modified to delete deleting the CMV promoter, and the PPE-1 promoter and Fas-c fragment were inserted by restriction digestion.

[0341] The modified PPE-1 promoter (PPE-1-3X, SEQ ID NO: 12) and the Fas-chimera transgene (Fas-c, SEQ ID NO: 4) were utilized for construction of the adenoviral vector. The PPE-1-(3X)-Fas-c element (2115 bp) was constructed from the PPE-1-(3X)-luc element. This element contains the 1.4 kb of the murine preproendothelin PPE-1-(3X) promoter, the Luciferase gene, the SV40 polyA site and the first intron of the murine ET-1 gene, originated from the pEL8 plasmid (8848 bp) used by Harats et al (Harats D. et al., JCI, 1995). The PPE-3-Luc cassette was extracted from the pEL8 plasmid using the BamHI restriction enzyme. The Luciferase gene was substituted by the Fas-c gene [composed of the extra cellular and intra membranal domains of the human TNF-R1 (Tumor Necrosis Factor Receptor 1, SEQ ID NO: 2) and of the Fas (p55) intracellular domain (SEQ ID NO: 3) (Boldin et al, JBC, 1995)] to obtain the PPE-1-3x-Fas-c cassette.

[0342] PPE-1(3x)-Fas-c Plasmid--The cassette was further introduced into the backbone plasmid by restriction digestion, resulting with the PPE-1(3x)-Fas-c plasmid.

[0343] Adaptor-PPE-1(3x)-Fas-c Plasmid--The PPE-1-3x-Fas-c element was extracted from the first generation construct PPE-1-3x-Fas-c plasmid, and was amplified with designated PCR primers introducing SnaB1 and EcoR1 restriction sites at the 5'-and-3'-end respectively. These sites were used to clone the PPE-Fas-c fragment into the adaptor plasmid digested with SnaB1 and EcoR1, resulting in the adaptor-PPE-1-3x-Fas-c used for transfection of the host cells (for example, PER.C6 cells).

[0344] Xenografts:

[0345] 10⁶ U87 human glioma tumor cells expressing a biofluorescent/bioluminescent protein (luciferase) were implanted intracranially in the striatum of athymic nude rats (NxGen BioSciences). Animals were anesthesized with isoflurane prior to implantation. Briefly, glioma tumor cells expressing luciferase were implanted intracranially in the striatum of athymic nude rats (NxGen BioSciences). Animals were anesthesized with isoflurane prior to implantation and placed secured on a Just for Mice Stereotaxic (Stoelting) apparatus. A 1 cm incision was made in the scalp and the bregma identified. A small burr hole was made in the cranium using a mounted Micromotor drill (Stoelting) at the identified position (1 mm forward and 4 mm lateral of the bregma). 1×10⁶ cells in a volume of 5 ul were injected into the caudate over 5 minutes using a Quintessential Stereotaxic Injector (Stoelting) containing a 10 ul Hamilton syringe mounted to the stereotaxic device to assure appropriate placement. Animals were imaged following isofluorane sedation using an IVIS chemiluminescence system. The fluorescence/bioluminescence of these tumors are typically detectable within 7-10 days due to rapid growth and high expression of the marker. An alternative imaging modality, i.e. MRI, was also utilized to assist with tumor visualization. Animals received chemical anesthesia for MRI imaging. Once tumor establishment and growth was detected (variable depending on the rate of growth for the respective line), rats were treated with VB-111. The total dose was 10¹¹ vp in a volume of 100 ul. Control groups received vehicle only. Animals were monitored for tumor growth or response through non-invasive imaging of fluorescence/luminescence--see FIG. 1 for a typical treatment and monitoring regimen.

[0346] Experimental Protocol:

[0347] Two types of tumor growth experiments were performed, tumor growth inhibition (TGI) and tumor growth delay (TGD). The TGI experiment was terminated when the animals showed clinical signs of tumor development i.e. become dull, listless, or moribund, usually prior to 4 weeks post-implantation, as median survival of 28-29 days has been typically observed in prior studies. Upon termination, all rats were weighed, sacrificed, and their tumors excised. For a TGD experiment, animals were sacrificed on an individual basis and tumor-related parameters (e.g. size) were measured. The average day of sacrifice was determined for all groups, and the tumor growth delay (TGD) for each treatment group compared to the control group was calculated.

[0348] MRI:

[0349] Magnetic resonance imaging has shown to be capable of demonstrating early changes within the tumor vasculature without any invasive measures. It is possible to generate maps of blood volume and blood flow, vascular permeability, white matter tracks, and apparent diffusion coefficient. These parameters offer clinically relevant physiological information that could help to characterize, stage tumor growth, and evaluate treatment efficacy. MRI was performed on a Bruker 7 Tesla scanner. Blood flow and blood volume was measured using dynamic contrast enhanced imaging technique following a bolus of gadopentetate-dimeglumine (GdDTPA). White matter tracks and apparent diffusion coefficient was measured using diffusion tensor imaging. Vascular permeability was measured using T1-weighted MRI obtained prior to and following contrast (Gd-DTPA) injection. For dynamic contrast enhanced MRI, single-shot gradient echo planar imaging (EPI) was used, resolution at 0.27×0.27×0.5 mm, 5 slices (no gap), matrix=96×96, field of view=25.6×25.6 mm, repetition time TR=0.5 s, echo time TE=20 ms. For diffusion tensor imaging, single-shot spin-echo echo-planar imaging was used, resolution be 0.27×0.27×0.5 mm, 15 slices (no gap), matrix=96×96, field of view=25.6×25.6 mm, repetition time TR=2 s, echo time TE=40 ms, b value=0 s/mm2, and 6 diffusion direction of b=1100 s/mm2. For T1-weighted MRI, conventional acquisition was used, resolution 0.27×0.27×0.5 mm, 15 slices (no gap), matrix=96×96, field of view=25.6×25.6 mm, repetition time TR=0.5 s, echo time TE=20 ms. The number of slices analyzed adequately covered the entire tumor region and roughly cover the entire cerebrum.

[0350] The maps described above were calculated using standard software. For permeability maps, the maps were processed using codes in Matlab to obtain maps of Ktrans (corresponding roughly to wash-in rates of the contrastagent. Ktrans can be influenced by flow, or by permeability, or both. In high-flow organs such as the brain, flow limitations are not usually a concern, but the blood-brain barrier severely limits permeability unless it is disrupted by disease. Even in such a state, Ktrans does not fully correspond to permeability, but it is related rather to the permeability*surface area product of the capillary bed (in nonflow-limited situations).

[0351] Histopathology:

[0352] To further characterize changes at the microscopic level, animals were sacrificed by cardiac puncture, followed by intracardiac saline and formalin irrigation. Necropsy was performed, and brains underwent standard H&E processing. The number of vessels per medium power field were counted.

[0353] Results

[0354] As illustrated in FIG. 2, animal death began at approximately day 32. The median survival for the control group was 39.25 (+/-3.8) days and for the treatment group was 45.8 days.

[0355] Luciferase Activity:

[0356] Luciferase activity was followed by ip injection of luciferin and optical imaging on a Xenogen system. The region of interest was generated automatically without manipulation and total photons recorded. As illustrated in FIG. 3, a clear separation in activity was observed at day 33 with a mean (SD) in the control group of 9.7 (2.9)×10⁶ versus 5.3 (6.2)×10⁵ in the treated group.

[0357] MRI:

[0358] As illustrated in FIG. 4, mean of the maximum diameters of tumors in the VB111 treated group was smaller than those for controls.

Example 2

Effect of VB-111 in Glioblastoma Patients

[0359] Treatment Plan:

[0360] VB-111 will be administered as a single intravenous infusion of 1×10¹² or 3×10¹² Dose.

[0361] Study consists of 2 cohorts.

[0362] Cohort 1a: 3-6 subjects, safety (1×10¹² VPs);

[0363] Cohort 1b: 3-6 subjects, safety (3×10¹² VPs);

[0364] Cohort 2: 23-26 subjects, efficacy & safety (3×10¹² VPs)

[0365] Cohort 1a & Cohort 1b: Study subjects will be enrolled sequentially. The first subject of each cohort will be treated and observed for 14 days; if no dose-limiting toxicities (DLT) are observed, then another two subjects will be recruited to that cohort. All six subjects of cohort 1 need to be observed for a minimum of 14 days and show no DLT for the start of the next cohort. If a DLT is observed in one patient in a specific dosing cohort, three additional subjects will be accrued for the same dosing cohort, and safety will be reassessed. If DLT is confirmed, i.e. two out of six subjects experience a DLT, then the study will be discontinued. All subjects in cohorts 1a and 1b must be observed for a minimum of 28 days prior to commencing cohort 2.

[0366] The study will be conducted according to the Simon's 2 step method. A total of 29 subjects are anticipated to enroll at the 3×10¹² VP dose level (3-6 from cohort 2 and 23-26 in cohort 3). Step one will include the first 10 patients at this dose level. A subject will be considered to have a response if s/he has either 6 months progression free survival or at least a partial tumor response according to Rano criteria. An interim analysis will be performed after 10 patients from cohorts 2 and 3 have completed the study. If 2 or more responses occur in the step 1 subjects, step 2 will commence, enrolling an additional 19 subjects.

[0367] The following study stopping rule for halting the study will be applied:

[0368] A) If 3 out of 6 (or 5 out of 9 or 6 out of 12) subjects in the cohort 1a & 1b experience drug related DLT.

[0369] B) If 2 out of the subjects in cohort 1a experience a DLT.

[0370] C) If ANY death occurs within two weeks after the product is given, except death due to disease progression or clearly unrelated to study drug. Enrollment will be temporarily suspended for an ad hoc, emergency IDMC meeting to review the case and make a recommendation if enrolment can be reinstated.

[0371] When safety end point is achieved for cohorts 1a and 1b (day 28), eligible subjects will be enrolled into the study and commence cohort 2. It is expected that 26 GBM subjects will be enrolled into cohort 2 for additional safety and efficacy endpoints (or 23 patients if 6 were enrolled in cohort 2).

[0372] One dose of VB 111 (1×10¹², 3×10¹² or 1×10¹³ VPs) administered within 3 weeks after the visit. Subjects will return to the clinic for follow up visits at days 4, 7, 14 and 28 and on monthly schedule on days 56, 84, 112, 140 and 168 if no disease progression has occurred prior to the visit.

[0373] On days 7, 14, 28, 56, 112 and 168, subjects will be assessed for response using contrast and non-contrast brain magnetic resonance imaging (MRI) with assessment based on the RANO criteria.

[0374] The post study follow up period will include telephone contacts every two months after day 168, early termination, or disease progression (whichever occurs earlier) to follow up on survival. Follow up will continue until patient expires. The study duration is 7 months (6 months post dose), thereafter the subjects will be followed by telephone for survival data every two months. Surveillance MRIs will be performed every 2 months until 1 year, and then every 3 months until 2 years post dosing (or until progression).

[0375] Population:

[0376] Up to 35 eligible subjects (cohort 1 & cohort 2) with relapsed GBM.

[0377] Main Inclusion Criteria:

[0378] 1. Ability to understand and the willingness to sign a written informed consent document.

[0379] 2. Subjects≧18 years of age

[0380] 3. Subjects must have histologically confirmed diagnosis of primary malignant glioma (glioblastoma multiforme, gliosarcoma or anaplastic astrocytoma, or anaplastic oligodendroglioma). Subjects with recurrent disease whose diagnostic pathology confirmed malignant glioma (glioblastoma multiforme, gliosarcoma or anaplastic astrocytoma, or anaplastic oligodendroglioma) will not need re-biopsy.

[0381] 4. Evidence of measurable recurrent or residual primary CNS neoplasm on contrast-enhanced MRI, unless medically contraindicated (CT scan will then be used).

[0382] 5. Measurable disease by RANO criteria.

[0383] 6. Avastin and anti-angiogenic (TKIs such as sunitinib or sorafenib) naive subjects.

[0384] 7. Disease progression or recurrence following standard of care treatment with radiotherapy and temozolomide.

[0385] 8. An interval of at least 4 weeks between prior surgical resection and study enrolment.

[0386] 9. Completed radiotherapy≧90 days before study starts.

[0387] 10. An interval of at least 12 weeks between prior radiotherapy or at least 4 weeks from prior chemotherapy, and enrolment on this protocol.

[0388] 11. Recovered to Grade 1 or less from the toxic effects of any earlier intervention.

[0389] 12. Karnofsky performance status a 60%.

[0390] 13. Adequate renal, liver, and bone marrow function according to the following criteria:

[0391] Absolute neutrophil count≧1500/mcL

[0392] Platelets≧125 000/mcL

[0393] Total bilirubin within upper limit of normal (ULN)

[0394] Aspartate aminotransferase (AST)≦2.5× institutional ULN

[0395] Creatinine within normal limits or creatinine clearance≧50 mL/min for patients with creatinine levels above normal limits.

[0396] PT, PTT greater than 80% of the lower normal limits.

[0397] 13. Subjects must be treated with corticosteroids on day 0. Subjects will be on a stable dose for 1 week prior to entry, and is not anticipated to require increase in steroid dose throughout the study.

[0398] 14. No evidence of haemorrhage on the baseline MRI or CT scan.

[0399] 15. Males and Females of childbearing potential must utilize, throughout the course of the trial a standard contraception method.

[0400] Cohort 1a and 1b Additional Eligibility Criteria: Subjects without Major Mass Effect of Tumor.

[0401] Main Exclusion Criteria:

[0402] 1. Pregnant or breastfeeding subjects

[0403] 2. Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids

[0404] 3. Active Infection.

[0405] 4. Greater than 3 prior recurrences.

[0406] 5. Evidence of CNS haemorrhage CTCAE on baseline MRI or CT scan.

[0407] 6. Requires therapeutic anti-coagulation.

[0408] 7. Prior anti-angiogenic therapy including VEGF-sequestering agents (e.g. bevicizumab, aflibercept) or VEGF inhibitors (e.g. cedirinib, pazopanib, sunitinib, sorafenib).

[0409] 8. Prior stereotactic radiotherapy.

[0410] 9. Known active secondary malignancy.

[0411] 10. Expected to have surgery during study period.

[0412] 11. Subjects, who suffered from an acute cardiac event within the last 12 months.

[0413] 12. Subjects with active vascular disease, either myocardial or peripheral

[0414] 13. Subjects with proliferative and/or vascular retinopathy

[0415] 14. Subjects with known liver disease (alcoholic, drug/toxin induced, genetic, or autoimmune).

[0416] 15. Subjects with known CNS metastatic disease (other than GBM).

[0417] 16. Subjects with known active second malignancy.

[0418] 17. Subjects testing positive to one of the following viruses: HIV, HBV and HCV

[0419] 18. Subjects that have undergone major surgery within the last 4 weeks before enrolment.

[0420] 19. Subjects may not have received any other investigational agent within 4 weeks before enrolment.

[0421] 20. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

[0422] Test Drug and Formulation:

[0423] VB-111 (SEQ ID NO: 9 or 10) is formulated as a sterile vector solution. The solution is supplied frozen (below -65° C.), in single use, plastic screw cap vials. Each vial contains 1.1 mL of vector solution at a viral titer of 1×10¹² VP/ml. The vector solution should be thawed and maintained on ice during dilution and handling for a maximum of 3 hours.

[0424] Dosage and Administration:

[0425] Prior to infusion, the solution for injection should be brought to room temperature Maximum time for drug in saline is 1 hour at room temperature. The vials should be opened in a biological safety cabinet and injected into 4 mL of normal saline for infusion for each 1 ml of drug. ie; for the 1×10¹² viral particle (VP) dose 1 ml of drug+4 ml of saline, for the 3×10¹² VP dose 3 ml of drug+12 ml of saline. A single infusion of approximately 5 mL/15 ml of diluted VB-111 should be administered 1 mL/minute.

[0426] Safety Evaluations:

[0427] Adverse events will be recorded on an ongoing basis and up to 2 months following the administration of the test drug. Adverse events will be assessed for seriousness, relatedness to study drug, and severity (according to CTCAE 4.0). Vital signs will be recorded at screening, prior to dosing, 30, 60 minutes, 4 and 6 hours after dosing and at all patient visits. A physical examination will be conducted at screening, days 14, 28, 56, 84, 112, 140, 168 and at the end of the study. A 12 lead ECG will be obtained at screening, prior to dosing and on days 28 and 168 (or ET). Safety laboratory assessment (blood haematology and chemistry, urine analysis) will be conducted at screening, prior to dosing, and at all patient visits, starting from day 4±1 to 168±7.

[0428] Distribution:

[0429] Blood and urine samples will be collected prior to dosing, at the end of the infusion, days 4, 7, 14, 28 and 56, for evaluation of levels of virus DNA (in whole blood and urine) and its transgene (in whole blood).

[0430] Tumor Response:

[0431] Tumor response will be assessed at screening, prior to dosing, days 14, 28, 56, 112, 140 and 168, and then every 2 months for 1 year and every 3 months for 2 years post dosing, using contrast and non-contrast brain magnetic resonance imaging (MRI) with assessment based on the RANO criteria, until progression of disease (local and central independent radiology review). For patients who do not progress or die, PFS will be censored at the time of initiation of alternative anticancer therapy, date of last radiologic assessment, or time of last contact.

[0432] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0433] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Sequence CWU 1

1

13134350DNAArtificial sequenceEmpty Ad5 vector sequence without repeats 1catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420cgggtcaaag ttggcgtttt attattatag tcagtacgtc tcgagcatgc atctaggcgg 480ccgcatggca gaaattcgcg aattcgctag cgttaacgga tcctctagac gagatccgaa 540cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa atttcacaaa 600taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca atgtatctta 660tcatgtctag atctgtactg aaatgtgtgg gcgtggctta agggtgggaa agaatatata 720aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg ccatgagcac 780caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc ccccatgggc 840cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc tgcccgcaaa 900ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg cagcctccgc 960cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg ctttcctgag 1020cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt tgacggctct 1080tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc agctgttgga 1140tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg tttaaaacat 1200aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct gtctttattt 1260aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga gggtcctgtg 1320tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg gcataagccc 1380gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg tgttgtagat 1440gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca gtagcaagct 1500gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct gggatgggtg 1560catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta tgttcccagc 1620catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc cggtgcactt 1680gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga cgcccttgtg 1740acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac gggcggcggc 1800ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga tgagatcgtc 1860ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa tggttccatc 1920cggcccaggg gcgtagttac cctcacagat ttaagggtgg gaaagaatat ataaggtggg 1980ggtcttatgt agttttgtat ctgttttgca gcagccgccg ccgccatgag caccaactcg 2040tttgatggaa gcattgtgag ctcatatttg acaacgcgca tgcccccatg ggccggggtg 2100cgtcagaatg tgatgggctc cagcattgat ggtcgccccg tcctgcccgc aaactctact 2160accttgacct acgagaccgt gtctggaacg ccgttggaga ctgcagcctc cgccgccgct 2220tcagccgctg cagccaccgc ccgcgggatt gtgactgact ttgctttcct gagcccgctt 2280gcaagcagtg cagcttcccg ttcatccgcc cgcgatgaca agttgacggc tcttttggca 2340caattggatt ctttgacccg ggaacttaat gtcgtttctc agcagctgtt ggatctgcgc 2400cagcaggttt ctgccctgaa ggcttcctcc cctcccaatg cggtttaaaa cataaataaa 2460aaaccagact ctgtttggat ttggatcaag caagtgtctt gctgtcttta tttaggggtt 2520ttgcgcgcgc ggtaggcccg ggaccagcgg tctcggtcgt tgagggtcct gtgtattttt 2580tccaggacgt ggtaaaggtg actctggatg ttcagataca tgggcataag cccgtctctg 2640gggtggaggt agcaccactg cagagcttca tgctgcgggg tggtgttgta gatgatccag 2700tcgtagcagg agcgctgggc gtggtgccta aaaatgtctt tcagtagcaa gctgattgcc 2760aggggcaggc ccttggtgta agtgtttaca aagcggttaa gctgggatgg gtgcatacgt 2820ggggatatga gatgcatctt ggactgtatt tttaggttgg ctatgttccc agccatatcc 2880ctccggggat tcatgttgtg cagaaccacc agcacagtgt atccggtgca cttgggaaat 2940ttgtcatgta gcttagaagg aaatgcgtgg aagaacttgg agacgccctt gtgacctcca 3000agattttcca tgcattcgtc cataatgatg gcaatgggcc cacgggcggc ggcctgggcg 3060aagatatttc tgggatcact aacgtcatag ttgtgttcca ggatgagatc gtcataggcc 3120atttttacaa agcgcgggcg gagggtgcca gactgcggta taatggttcc atccggccca 3180ggggcgtagt taccctcaca gatttgcatt tcccacgctt tgagttcaga tggggggatc 3240atgtctacct gcggggcgat gaagaaaacg gtttccgggg taggggagat cagctgggaa 3300gaaagcaggt tcctgagcag ctgcgactta ccgcagccgg tgggcccgta aatcacacct 3360attaccggct gcaactggta gttaagagag ctgcagctgc cgtcatccct gagcaggggg 3420gccacttcgt taagcatgtc cctgactcgc atgttttccc tgaccaaatc cgccagaagg 3480cgctcgccgc ccagcgatag cagttcttgc aaggaagcaa agtttttcaa cggtttgaga 3540ccgtccgccg taggcatgct tttgagcgtt tgaccaagca gttccaggcg gtcccacagc 3600tcggtcacct gctctacggc atctcgatcc agcatatctc ctcgtttcgc gggttggggc 3660ggctttcgct gtacggcagt agtcggtgct cgtccagacg ggccagggtc atgtctttcc 3720acgggcgcag ggtcctcgtc agcgtagtct gggtcacggt gaaggggtgc gctccgggct 3780gcgcgctggc cagggtgcgc ttgaggctgg tcctgctggt gctgaagcgc tgccggtctt 3840cgccctgcgc gtcggccagg tagcatttga ccatggtgtc atagtccagc ccctccgcgg 3900cgtggccctt ggcgcgcagc ttgcccttgg aggaggcgcc gcacgagggg cagtgcagac 3960ttttgagggc gtagagcttg ggcgcgagaa ataccgattc cggggagtag gcatccgcgc 4020cgcaggcccc gcagacggtc tcgcattcca cgagccaggt gagctctggc cgttcggggt 4080caaaaaccag gtttccccca tgctttttga tgcgtttctt acctctggtt tccatgagcc 4140ggtgtccacg ctcggtgacg aaaaggctgt ccgtgtcccc gtatacagac ttgagaggcc 4200tgtcctcgag cggtgttccg cggtcctcct cgtatagaaa ctcggaccac tctgagacaa 4260aggctcgcgt ccaggccagc acgaaggagg ctaagtggga ggggtagcgg tcgttgtcca 4320ctagggggtc cactcgctcc agggtgtgaa gacacatgtc gccctcttcg gcatcaagga 4380aggtgattgg tttgtaggtg taggccacgt gaccgggtgt tcctgaaggg gggctataaa 4440agggggtggg ggcgcgttcg tcctcactct cttccgcatc gctgtctgcg agggccagct 4500gttggggtga gtactccctc tgaaaagcgg gcatgacttc tgcgctaaga ttgtcagttt 4560ccaaaaacga ggaggatttg atattcacct ggcccgcggt gatgcctttg agggtggccg 4620catccatctg gtcagaaaag acaatctttt tgttgtcaag cttggtggca aacgacccgt 4680agagggcgtt ggacagcaac ttggcgatgg agcgcagggt ttggtttttg tcgcgatcgg 4740cgcgctcctt ggccgcgatg tttagctgca cgtattcgcg cgcaacgcac cgccattcgg 4800gaaagacggt ggtgcgctcg tcgggcacca ggtgcacgcg ccaaccgcgg ttgtgcaggg 4860tgacaaggtc aacgctggtg gctacctctc cgcgtaggcg ctcgttggtc cagcagaggc 4920ggccgccctt gcgcgagcag aatggcggta gggggtctag ctgcgtctcg tccggggggt 4980ctgcgtccac ggtaaagacc ccgggcagca ggcgcgcgtc gaagtagtct atcttgcatc 5040cttgcaagtc tagcgcctgc tgccatgcgc gggcggcaag cgcgcgctcg tatgggttga 5100gtgggggacc ccatggcatg gggtgggtga gcgcggaggc gtacatgccg caaatgtcgt 5160aaacgtagag gggctctctg agtattccaa gatatgtagg gtagcatctt ccaccgcgga 5220tgctggcgcg cacgtaatcg tatagttcgt gcgagggagc gaggaggtcg ggaccgaggt 5280tgctacgggc gggctgctct gctcggaaga ctatctgcct gaagatggca tgtgagttgg 5340atgatatggt tggacgctgg aagacgttga agctggcgtc tgtgagacct accgcgtcac 5400gcacgaagga ggcgtaggag tcgcgcagct tgttgaccag ctcggcggtg acctgcacgt 5460ctagggcgca gtagtccagg gtttccttga tgatgtcata cttatcctgt cccttttttt 5520tccacagctc gcggttgagg acaaactctt cgcggtcttt ccagtactct tggatcggaa 5580acccgtcggc ctccgaacgg taagagccta gcatgtagaa ctggttgacg gcctggtagg 5640cgcagcatcc cttttctacg ggtagcgcgt atgcctgcgc ggccttccgg agcgaggtgt 5700gggtgagcgc aaaggtgtcc ctgaccatga ctttgaggta ctggtatttg aagtcagtgt 5760cgtcgcatcc gccctgctcc cagagcaaaa agtccgtgcg ctttttggaa cgcggatttg 5820gcagggcgaa ggtgacatcg ttgaagagta tctttcccgc gcgaggcata aagttgcgtg 5880tgatgcggaa gggtcccggc acctcggaac ggttgttaat tacctgggcg gcgagcacga 5940tctcgtcaaa gccgttgatg ttgtggccca caatgtaaag ttccaagaag cgcgggatgc 6000ccttgatgga aggcaatttt ttaagttcct cgtaggtgag ctcttcaggg gagctgagcc 6060cgtgctctga aagggcccag tctgcaagat gagggttgga agcgacgaat gagctccaca 6120ggtcacgggc cattagcatt tgcaggtggt cgcgaaaggt cctaaactgg cgacctatgg 6180ccattttttc tggggtgatg cagtagaagg taagcgggtc ttgttcccag cggtcccatc 6240caaggttcgc ggctaggtct cgcgcggcag tcactagagg ctcatctccg ccgaacttca 6300tgaccagcat gaagggcacg agctgcttcc caaaggcccc catccaagta taggtctcta 6360catcgtaggt gacaaagaga cgctcggtgc gaggatgcga gccgatcggg aagaactgga 6420tctcccgcca ccaattggag gagtggctat tgatgtggtg aaagtagaag tccctgcgac 6480gggccgaaca ctcgtgctgg cttttgtaaa aacgtgcgca gtactggcag cggtgcacgg 6540gctgtacatc ctgcacgagg ttgacctgac gaccgcgcac aaggaagcag agtgggaatt 6600tgagcccctc gcctggcggg tttggctggt ggtcttctac ttcggctgct tgtccttgac 6660cgtctggctg ctcgagggga gttacggtgg atcggaccac cacgccgcgc gagcccaaag 6720tccagatgtc cgcgcgcggc ggtcggagct tgatgacaac atcgcgcaga tgggagctgt 6780ccatggtctg gagctcccgc ggcgtcaggt caggcgggag ctcctgcagg tttacctcgc 6840atagacgggt cagggcgcgg gctagatcca ggtgatacct aatttccagg ggctggttgg 6900tggcggcgtc gatggcttgc aagaggccgc atccccgcgg cgcgactacg gtaccgcgcg 6960gcgggcggtg ggccgcgggg gtgtccttgg atgatgcatc taaaagcggt gacgcgggcg 7020agcccccgga ggtagggggg gctccggacc cgccgggaga gggggcaggg gcacgtcggc 7080gccgcgcgcg ggcaggagct ggtgctgcgc gcgtaggttg ctggcgaacg cgacgacgcg 7140gcggttgatc tcctgaatct ggcgcctctg cgtgaagacg acgggcccgg tgagcttgaa 7200cctgaaagag agttcgacag aatcaatttc ggtgtcgttg acggcggcct ggcgcaaaat 7260ctcctgcacg tctcctgagt tgtcttgata ggcgatctcg gccatgaact gctcgatctc 7320ttcctcctgg agatctccgc gtccggctcg ctccacggtg gcggcgaggt cgttggaaat 7380gcgggccatg agctgcgaga aggcgttgag gcctccctcg ttccagacgc ggctgtagac 7440cacgccccct tcggcatcgc gggcgcgcat gaccacctgc gcgagattga gctccacgtg 7500ccgggcgaag acggcgtagt ttcgcaggcg ctgaaagagg tagttgaggg tggtggcggt 7560gtgttctgcc acgaagaagt acataaccca gcgtcgcaac gtggattcgt tgatatcccc 7620caaggcctca aggcgctcca tggcctcgta gaagtccacg gcgaagttga aaaactggga 7680gttgcgcgcc gacacggtta actcctcctc cagaagacgg atgagctcgg cgacagtgtc 7740gcgcacctcg cgctcaaagg ctacaggggc ctcttcttct tcttcaatct cctcttccat 7800aagggcctcc ccttcttctt cttctggcgg cggtggggga ggggggacac ggcggcgacg 7860acggcgcacc gggaggcggt cgacaaagcg ctcgatcatc tccccgcggc gacggcgcat 7920ggtctcggtg acggcgcggc cgttctcgcg ggggcgcagt tggaagacgc cgcccgtcat 7980gtcccggtta tgggttggcg gggggctgcc atgcggcagg gatacggcgc taacgatgca 8040tctcaacaat tgttgtgtag gtactccgcc gccgagggac ctgagcgagt ccgcatcgac 8100cggatcggaa aacctctcga gaaaggcgtc taaccagtca cagtcgcaag gtaggctgag 8160caccgtggcg ggcggcagcg ggcggcggtc ggggttgttt ctggcggagg tgctgctgat 8220gatgtaatta aagtaggcgg tcttgagacg gcggatggtc gacagaagca ccatgtcctt 8280gggtccggcc tgctgaatgc gcaggcggtc ggccatgccc caggcttcgt tttgacatcg 8340gcgcaggtct ttgtagtagt cttgcatgag cctttctacc ggcacttctt cttctccttc 8400ctcttgtcct gcatctcttg catctatcgc tgcggcggcg gcggagtttg gccgtaggtg 8460gcgccctctt cctcccatgc gtgtgacccc gaagcccctc atcggctgaa gcagggctag 8520gtcggcgaca acgcgctcgg ctaatatggc ctgctgcacc tgcgtgaggg tagactggaa 8580gtcatccatg tccacaaagc ggtggtatgc gcccgtgttg atggtgtaag tgcagttggc 8640cataacggac cagttaacgg tctggtgacc cggctgcgag agctcggtgt acctgagacg 8700cgagtaagcc ctcgagtcaa atacgtagtc gttgcaagtc cgcaccaggt actggtatcc 8760caccaaaaag tgcggcggcg gctggcggta gaggggccag cgtagggtgg ccggggctcc 8820gggggcgaga tcttccaaca taaggcgatg atatccgtag atgtacctgg acatccaggt 8880gatgccggcg gcggtggtgg aggcgcgcgg aaagtcgcgg acgcggttcc agatgttgcg 8940cagcggcaaa aagtgctcca tggtcgggac gctctggccg gtcaggcgcg cgcaatcgtt 9000gacgctctag accgtgcaaa aggagagcct gtaagcgggc actcttccgt ggtctggtgg 9060ataaattcgc aagggtatca tggcggacga ccggggttcg agccccgtat ccggccgtcc 9120gccgtgatcc atgcggttac cgcccgcgtg tcgaacccag gtgtgcgacg tcagacaacg 9180ggggagtgct ccttttggct tccttccagg cgcggcggct gctgcgctag cttttttggc 9240cactggccgc gcgcagcgta agcggttagg ctggaaagcg aaagcattaa gtggctcgct 9300ccctgtagcc ggagggttat tttccaaggg ttgagtcgcg ggacccccgg ttcgagtctc 9360ggaccggccg gactgcggcg aacgggggtt tgcctccccg tcatgcaaga ccccgcttgc 9420aaattcctcc ggaaacaggg acgagcccct tttttgcttt tcccagatgc atccggtgct 9480gcggcagatg cgcccccctc ctcagcagcg gcaagagcaa gagcagcggc agacatgcag 9540ggcaccctcc cctcctccta ccgcgtcagg aggggcgaca tccgcggttg acgcggcagc 9600agatggtgat tacgaacccc cgcggcgccg ggcccggcac tacctggact tggaggaggg 9660cgagggcctg gcgcggctag gagcgccctc tcctgagcgg cacccaaggg tgcagctgaa 9720gcgtgatacg cgtgaggcgt acgtgccgcg gcagaacctg tttcgcgacc gcgagggaga 9780ggagcccgag gagatgcggg atcgaaagtt ccacgcaggg cgcgagctgc ggcatggcct 9840gaatcgcgag cggttgctgc gcgaggagga ctttgagccc gacgcgcgaa ccgggattag 9900tcccgcgcgc gcacacgtgg cggccgccga cctggtaacc gcatacgagc agacggtgaa 9960ccaggagatt aactttcaaa aaagctttaa caaccacgtg cgtacgcttg tggcgcgcga 10020ggaggtggct ataggactga tgcatctgtg ggactttgta agcgcgctgg agcaaaaccc 10080aaatagcaag ccgctcatgg cgcagctgtt ccttatagtg cagcacagca gggacaacga 10140ggcattcagg gatgcgctgc taaacatagt agagcccgag ggccgctggc tgctcgattt 10200gataaacatc ctgcagagca tagtggtgca ggagcgcagc ttgagcctgg ctgacaaggt 10260ggccgccatc aactattcca tgcttagcct gggcaagttt tacgcccgca agatatacca 10320taccccttac gttcccatag acaaggaggt aaagatcgag gggttctaca tgcgcatggc 10380gctgaaggtg cttaccttga gcgacgacct gggcgtttat cgcaacgagc gcatccacaa 10440ggccgtgagc gtgagccggc ggcgcgagct cagcgaccgc gagctgatgc acagcctgca 10500aagggccctg gctggcacgg gcagcggcga tagagaggcc gagtcctact ttgacgcggg 10560cgctgacctg cgctgggccc caagccgacg cgccctggag gcagctgggg ccggacctgg 10620gctggcggtg gcacccgcgc gcgctggcaa cgtcggcggc gtggaggaat atgacgagga 10680cgatgagtac gagccagagg acggcgagta ctaagcggtg atgtttctga tcagatgatg 10740caagacgcaa cggacccggc ggtgcgggcg gcgctgcaga gccagccgtc cggccttaac 10800tccacggacg actggcgcca ggtcatggac cgcatcatgt cgctgactgc gcgcaatcct 10860gacgcgttcc ggcagcagcc gcaggccaac cggctctccg caattctgga agcggtggtc 10920ccggcgcgcg caaaccccac gcacgagaag gtgctggcga tcgtaaacgc gctggccgaa 10980aacagggcca tccggcccga cgaggccggc ctggtctacg acgcgctgct tcagcgcgtg 11040gctcgttaca acagcggcaa cgtgcagacc aacctggacc ggctggtggg ggatgtgcgc 11100gaggccgtgg cgcagcgtga gcgcgcgcag cagcagggca acctgggctc catggttgca 11160ctaaacgcct tcctgagtac acagcccgcc aacgtgccgc ggggacagga ggactacacc 11220aactttgtga gcgcactgcg gctaatggtg actgagacac cgcaaagtga ggtgtaccag 11280tctgggccag actatttttt ccagaccagt agacaaggcc tgcagaccgt aaacctgagc 11340caggctttca aaaacttgca ggggctgtgg ggggtgcggg ctcccacagg cgaccgcgcg 11400accgtgtcta gcttgctgac gcccaactcg cgcctgttgc tgctgctaat agcgcccttc 11460acggacagtg gcagcgtgtc ccgggacaca tacctaggtc acttgctgac actgtaccgc 11520gaggccatag gtcaggcgca tgtggacgag catactttcc aggagattac aagtgtcagc 11580cgcgcgctgg ggcaggagga cacgggcagc ctggaggcaa ccctaaacta cctgctgacc 11640aaccggcggc agaagatccc ctcgttgcac agtttaaaca gcgaggagga gcgcattttg 11700cgctacgtgc agcagagcgt gagccttaac ctgatgcgcg acggggtaac gcccagcgtg 11760gcgctggaca tgaccgcgcg caacatggaa ccgggcatgt atgcctcaaa ccggccgttt 11820atcaaccgcc taatggacta cttgcatcgc gcggccgccg tgaaccccga gtatttcacc 11880aatgccatct tgaacccgca ctggctaccg ccccctggtt tctacaccgg gggattcgag 11940gtgcccgagg gtaacgatgg attcctctgg gacgacatag acgacagcgt gttttccccg 12000caaccgcaga ccctgctaga gttgcaacag cgcgagcagg cagaggcggc gctgcgaaag 12060gaaagcttcc gcaggccaag cagcttgtcc gatctaggcg ctgcggcccc gcggtcagat 12120gctagtagcc catttccaag cttgataggg tctcttacca gcactcgcac cacccgcccg 12180cgcctgctgg gcgaggagga gtacctaaac aactcgctgc tgcagccgca gcgcgaaaaa 12240aacctgcctc cggcatttcc caacaacggg atagagagcc tagtggacaa gatgagtaga 12300tggaagacgt acgcgcagga gcacagggac gtgccaggcc cgcgcccgcc cacccgtcgt 12360caaaggcacg accgtcagcg gggtctggtg tgggaggacg atgactcggc agacgacagc 12420agcgtcctgg atttgggagg gagtggcaac ccgtttgcgc accttcgccc caggctgggg 12480agaatgtttt aaaaaaaaaa aaagcatgat gcaaaataaa aaactcacca aggccatggc 12540accgagcgtt ggttttcttg tattcccctt agtatgcggc gcgcggcgat gtatgaggaa 12600ggtcctcctc cctcctacga gagtgtggtg agcgcggcgc cagtggcggc ggcgctgggt 12660tctcccttcg atgctcccct ggacccgccg tttgtgcctc cgcggtacct gcggcctacc 12720ggggggagaa acagcatccg ttactctgag ttggcacccc tattcgacac cacccgtgtg 12780tacctggtgg acaacaagtc aacggatgtg gcatccctga actaccagaa cgaccacagc 12840aactttctga ccacggtcat tcaaaacaat gactacagcc cgggggaggc aagcacacag 12900accatcaatc ttgacgaccg gtcgcactgg ggcggcgacc tgaaaaccat cctgcatacc 12960aacatgccaa atgtgaacga gttcatgttt accaataagt ttaaggcgcg ggtgatggtg 13020tcgcgcttgc ctactaagga caatcaggtg gagctgaaat acgagtgggt ggagttcacg 13080ctgcccgagg gcaactactc cgagaccatg accatagacc ttatgaacaa cgcgatcgtg 13140gagcactact tgaaagtggg cagacagaac ggggttctgg aaagcgacat cggggtaaag 13200tttgacaccc gcaacttcag actggggttt gaccccgtca ctggtcttgt catgcctggg 13260gtatatacaa acgaagcctt ccatccagac atcattttgc tgccaggatg cggggtggac 13320ttcacccaca gccgcctgag caacttgttg ggcatccgca agcggcaacc cttccaggag 13380ggctttagga tcacctacga tgatctggag ggtggtaaca ttcccgcact gttggatgtg 13440gacgcctacc aggcgagctt gaaagatgac accgaacagg gcgggggtgg cgcaggcggc 13500agcaacagca gtggcagcgg cgcggaagag aactccaacg cggcagccgc ggcaatgcag 13560ccggtggagg acatgaacga tcatgccatt cgcggcgaca cctttgccac acgggctgag 13620gagaagcgcg ctgaggccga agcagcggcc gaagctgccg cccccgctgc gcaacccgag 13680gtcgagaagc ctcagaagaa accggtgatc aaacccctga cagaggacag caagaaacgc 13740agttacaacc taataagcaa tgacagcacc ttcacccagt accgcagctg gtaccttgca 13800tacaactacg gcgaccctca gaccggaatc cgctcatgga ccctgctttg cactcctgac 13860gtaacctgcg gctcggagca ggtctactgg tcgttgccag acatgatgca agaccccgtg 13920accttccgct ccacgcgcca gatcagcaac tttccggtgg tgggcgccga gctgttgccc 13980gtgcactcca agagcttcta caacgaccag gccgtctact cccaactcat ccgccagttt 14040acctctctga cccacgtgtt caatcgcttt cccgagaacc agattttggc gcgcccgcca 14100gcccccacca tcaccaccgt cagtgaaaac gttcctgctc tcacagatca cgggacgcta 14160ccgctgcgca acagcatcgg aggagtccag cgagtgacca ttactgacgc cagacgccgc 14220acctgcccct acgtttacaa ggccctgggc atagtctcgc cgcgcgtcct atcgagccgc 14280actttttgag caagcatgtc catccttata tcgcccagca ataacacagg ctggggcctg 14340cgcttcccaa gcaagatgtt tggcggggcc aagaagcgct ccgaccaaca cccagtgcgc 14400gtgcgcgggc actaccgcgc gccctggggc gcgcacaaac gcggccgcac tgggcgcacc 14460accgtcgatg acgccatcga cgcggtggtg gaggaggcgc gcaactacac gcccacgccg 14520ccaccagtgt ccacagtgga cgcggccatt cagaccgtgg tgcgcggagc ccggcgctat 14580gctaaaatga agagacggcg gaggcgcgta gcacgtcgcc accgccgccg acccggcact 14640gccgcccaac gcgcggcggc ggccctgctt aaccgcgcac gtcgcaccgg ccgacgggcg 14700gccatgcggg ccgctcgaag gctggccgcg ggtattgtca ctgtgccccc caggtccagg 14760cgacgagcgg ccgccgcagc agccgcggcc attagtgcta tgactcaggg tcgcaggggc 14820aacgtgtatt gggtgcgcga ctcggttagc ggcctgcgcg tgcccgtgcg cacccgcccc 14880ccgcgcaact agattgcaag aaaaaactac ttagactcgt actgttgtat gtatccagcg 14940gcggcggcgc gcaacgaagc tatgtccaag cgcaaaatca aagaagagat gctccaggtc

15000atcgcgccgg agatctatgg ccccccgaag aaggaagagc aggattacaa gccccgaaag 15060ctaaagcggg tcaaaaagaa aaagaaagat gatgatgatg aacttgacga cgaggtggaa 15120ctgctgcacg ctaccgcgcc caggcgacgg gtacagtgga aaggtcgacg cgtaaaacgt 15180gttttgcgac ccggcaccac cgtagtcttt acgcccggtg agcgctccac ccgcacctac 15240aagcgcgtgt atgatgaggt gtacggcgac gaggacctgc ttgagcaggc caacgagcgc 15300ctcggggagt ttgcctacgg aaagcggcat aaggacatgc tggcgttgcc gctggacgag 15360ggcaacccaa cacctagcct aaagcccgta acactgcagc aggtgctgcc cgcgcttgca 15420ccgtccgaag aaaagcgcgg cctaaagcgc gagtctggtg acttggcacc caccgtgcag 15480ctgatggtac ccaagcgcca gcgactggaa gatgtcttgg aaaaaatgac cgtggaacct 15540gggctggagc ccgaggtccg cgtgcggcca atcaagcagg tggcgccggg actgggcgtg 15600cagaccgtgg acgttcagat acccactacc agtagcacca gtattgccac cgccacagag 15660ggcatggaga cacaaacgtc cccggttgcc tcagcggtgg cggatgccgc ggtgcaggcg 15720gtcgctgcgg ccgcgtccaa gacctctacg gaggtgcaaa cggacccgtg gatgtttcgc 15780gtttcagccc cccggcgccc gcgccgttcg aggaagtacg gcgccgccag cgcgctactg 15840cccgaatatg ccctacatcc ttccattgcg cctacccccg gctatcgtgg ctacacctac 15900cgccccagaa gacgagcaac tacccgacgc cgaaccacca ctggaacccg ccgccgccgt 15960cgccgtcgcc agcccgtgct ggccccgatt tccgtgcgca gggtggctcg cgaaggaggc 16020aggaccctgg tgctgccaac agcgcgctac caccccagca tcgtttaaaa gccggtcttt 16080gtggttcttg cagatatggc cctcacctgc cgcctccgtt tcccggtgcc gggattccga 16140ggaagaatgc accgtaggag gggcatggcc ggccacggcc tgacgggcgg catgcgtcgt 16200gcgcaccacc ggcggcggcg cgcgtcgcac cgtcgcatgc gcggcggtat cctgcccctc 16260cttattccac tgatcgccgc ggcgattggc gccgtgcccg gaattgcatc cgtggccttg 16320caggcgcaga gacactgatt aaaaacaagt tgcatgtgga aaaatcaaaa taaaaagtct 16380ggactctcac gctcgcttgg tcctgtaact attttgtaga atggaagaca tcaactttgc 16440gtctctggcc ccgcgacacg gctcgcgccc gttcatggga aactggcaag atatcggcac 16500cagcaatatg agcggtggcg ccttcagctg gggctcgctg tggagcggca ttaaaaattt 16560cggttccacc gttaagaact atggcagcaa ggcctggaac agcagcacag gccagatgct 16620gagggataag ttgaaagagc aaaatttcca acaaaaggtg gtagatggcc tggcctctgg 16680cattagcggg gtggtggacc tggccaacca ggcagtgcaa aataagatta acagtaagct 16740tgatccccgc cctcccgtag aggagcctcc accggccgtg gagacagtgt ctccagaggg 16800gcgtggcgaa aagcgtccgc gccccgacag ggaagaaact ctggtgacgc aaatagacga 16860gcctccctcg tacgaggagg cactaaagca aggcctgccc accacccgtc ccatcgcgcc 16920catggctacc ggagtgctgg gccagcacac acccgtaacg ctggacctgc ctccccccgc 16980cgacacccag cagaaacctg tgctgccagg cccgaccgcc gttgttgtaa cccgtcctag 17040ccgcgcgtcc ctgcgccgcg ccgccagcgg tccgcgatcg ttgcggcccg tagccagtgg 17100caactggcaa agcacactga acagcatcgt gggtctgggg gtgcaatccc tgaagcgccg 17160acgatgcttc tgatagctaa cgtgtcgtat gtgtgtcatg tatgcgtcca tgtcgccgcc 17220agaggagctg ctgagccgcc gcgcgcccgc tttccaagat ggctacccct tcgatgatgc 17280cgcagtggtc ttacatgcac atctcgggcc aggacgcctc ggagtacctg agccccgggc 17340tggtgcagtt tgcccgcgcc accgagacgt acttcagcct gaataacaag tttagaaacc 17400ccacggtggc gcctacgcac gacgtgacca cagaccggtc ccagcgtttg acgctgcggt 17460tcatccctgt ggaccgtgag gatactgcgt actcgtacaa ggcgcggttc accctagctg 17520tgggtgataa ccgtgtgctg gacatggctt ccacgtactt tgacatccgc ggcgtgctgg 17580acaggggccc tacttttaag ccctactctg gcactgccta caacgccctg gctcccaagg 17640gtgccccaaa tccttgcgaa tgggatgaag ctgctactgc tcttgaaata aacctagaag 17700aagaggacga tgacaacgaa gacgaagtag acgagcaagc tgagcagcaa aaaactcacg 17760tatttgggca ggcgccttat tctggtataa atattacaaa ggagggtatt caaataggtg 17820tcgaaggtca aacacctaaa tatgccgata aaacatttca acctgaacct caaataggag 17880aatctcagtg gtacgaaaca gaaattaatc atgcagctgg gagagtccta aaaaagacta 17940ccccaatgaa accatgttac ggttcatatg caaaacccac aaatgaaaat ggagggcaag 18000gcattcttgt aaagcaacaa aatggaaagc tagaaagtca agtggaaatg caatttttct 18060caactactga ggcagccgca ggcaatggtg ataacttgac tcctaaagtg gtattgtaca 18120gtgaagatgt agatatagaa accccagaca ctcatatttc ttacatgccc actattaagg 18180aaggtaactc acgagaacta atgggccaac aatctatgcc caacaggcct aattacattg 18240cttttaggga caattttatt ggtctaatgt attacaacag cacgggtaat atgggtgttc 18300tggcgggcca agcatcgcag ttgaatgctg ttgtagattt gcaagacaga aacacagagc 18360tttcatacca gcttttgctt gattccattg gtgatagaac caggtacttt tctatgtgga 18420atcaggctgt tgacagctat gatccagatg ttagaattat tgaaaatcat ggaactgaag 18480atgaacttcc aaattactgc tttccactgg gaggtgtgat taatacagag actcttacca 18540aggtaaaacc taaaacaggt caggaaaatg gatgggaaaa agatgctaca gaattttcag 18600ataaaaatga aataagagtt ggaaataatt ttgccatgga aatcaatcta aatgccaacc 18660tgtggagaaa tttcctgtac tccaacatag cgctgtattt gcccgacaag ctaaagtaca 18720gtccttccaa cgtaaaaatt tctgataacc caaacaccta cgactacatg aacaagcgag 18780tggtggctcc cgggctagtg gactgctaca ttaaccttgg agcacgctgg tcccttgact 18840atatggacaa cgtcaaccca tttaaccacc accgcaatgc tggcctgcgc taccgctcaa 18900tgttgctggg caatggtcgc tatgtgccct tccacatcca ggtgcctcag aagttctttg 18960ccattaaaaa cctccttctc ctgccgggct catacaccta cgagtggaac ttcaggaagg 19020atgttaacat ggttctgcag agctccctag gaaatgacct aagggttgac ggagccagca 19080ttaagtttga tagcatttgc ctttacgcca ccttcttccc catggcccac aacaccgcct 19140ccacgcttga ggccatgctt agaaacgaca ccaacgacca gtcctttaac gactatctct 19200ccgccgccaa catgctctac cctatacccg ccaacgctac caacgtgccc atatccatcc 19260cctcccgcaa ctgggcggct ttccgcggct gggccttcac gcgccttaag actaaggaaa 19320ccccatcact gggctcgggc tacgaccctt attacaccta ctctggctct ataccctacc 19380tagatggaac cttttacctc aaccacacct ttaagaaggt ggccattacc tttgactctt 19440ctgtcagctg gcctggcaat gaccgcctgc ttacccccaa cgagtttgaa attaagcgct 19500cagttgacgg ggagggttac aacgttgccc agtgtaacat gaccaaagac tggttcctgg 19560tacaaatgct agctaactat aacattggct accagggctt ctatatccca gagagctaca 19620aggaccgcat gtactccttc tttagaaact tccagcccat gagccgtcag gtggtggatg 19680atactaaata caaggactac caacaggtgg gcatcctaca ccaacacaac aactctggat 19740ttgttggcta ccttgccccc accatgcgcg aaggacaggc ctaccctgct aacttcccct 19800atccgcttat aggcaagacc gcagttgaca gcattaccca gaaaaagttt ctttgcgatc 19860gcaccctttg gcgcatccca ttctccagta actttatgtc catgggcgca ctcacagacc 19920tgggccaaaa ccttctctac gccaactccg cccacgcgct agacatgact tttgaggtgg 19980atcccatgga cgagcccacc cttctttatg ttttgtttga agtctttgac gtggtccgtg 20040tgcaccagcc gcaccgcggc gtcatcgaaa ccgtgtacct gcgcacgccc ttctcggccg 20100gcaacgccac aacataaaga agcaagcaac atcaacaaca gctgccgcca tgggctccag 20160tgagcaggaa ctgaaagcca ttgtcaaaga tcttggttgt gggccatatt ttttgggcac 20220ctatgacaag cgctttccag gctttgtttc tccacacaag ctcgcctgcg ccatagtcaa 20280tacggccggt cgcgagactg ggggcgtaca ctggatggcc tttgcctgga acccgcactc 20340aaaaacatgc tacctctttg agccctttgg cttttctgac cagcgactca agcaggttta 20400ccagtttgag tacgagtcac tcctgcgccg tagcgccatt gcttcttccc ccgaccgctg 20460tataacgctg gaaaagtcca cccaaagcgt acaggggccc aactcggccg cctgtggact 20520attctgctgc atgtttctcc acgcctttgc caactggccc caaactccca tggatcacaa 20580ccccaccatg aaccttatta ccggggtacc caactccatg ctcaacagtc cccaggtaca 20640gcccaccctg cgtcgcaacc aggaacagct ctacagcttc ctggagcgcc actcgcccta 20700cttccgcagc cacagtgcgc agattaggag cgccacttct ttttgtcact tgaaaaacat 20760gtaaaaataa tgtactagag acactttcaa taaaggcaaa tgcttttatt tgtacactct 20820cgggtgatta tttaccccca cccttgccgt ctgcgccgtt taaaaatcaa aggggttctg 20880ccgcgcatcg ctatgcgcca ctggcaggga cacgttgcga tactggtgtt tagtgctcca 20940cttaaactca ggcacaacca tccgcggcag ctcggtgaag ttttcactcc acaggctgcg 21000caccatcacc aacgcgttta gcaggtcggg cgccgatatc ttgaagtcgc agttggggcc 21060tccgccctgc gcgcgcgagt tgcgatacac agggttgcag cactggaaca ctatcagcgc 21120cgggtggtgc acgctggcca gcacgctctt gtcggagatc agatccgcgt ccaggtcctc 21180cgcgttgctc agggcgaacg gagtcaactt tggtagctgc cttcccaaaa agggcgcgtg 21240cccaggcttt gagttgcact cgcaccgtag tggcatcaaa aggtgaccgt gcccggtctg 21300ggcgttagga tacagcgcct gcataaaagc cttgatctgc ttaaaagcca cctgagcctt 21360tgcgccttca gagaagaaca tgccgcaaga cttgccggaa aactgattgg ccggacaggc 21420cgcgtcgtgc acgcagcacc ttgcgtcggt gttggagatc tgcaccacat ttcggcccca 21480ccggttcttc acgatcttgg ccttgctaga ctgctccttc agcgcgcgct gcccgttttc 21540gctcgtcaca tccatttcaa tcacgtgctc cttatttatc ataatgcttc cgtgtagaca 21600cttaagctcg ccttcgatct cagcgcagcg gtgcagccac aacgcgcagc ccgtgggctc 21660gtgatgcttg taggtcacct ctgcaaacga ctgcaggtac gcctgcagga atcgccccat 21720catcgtcaca aaggtcttgt tgctggtgaa ggtcagctgc aacccgcggt gctcctcgtt 21780cagccaggtc ttgcatacgg ccgccagagc ttccacttgg tcaggcagta gtttgaagtt 21840cgcctttaga tcgttatcca cgtggtactt gtccatcagc gcgcgcgcag cctccatgcc 21900cttctcccac gcagacacga tcggcacact cagcgggttc atcaccgtaa tttcactttc 21960cgcttcgctg ggctcttcct cttcctcttg cgtccgcata ccacgcgcca ctgggtcgtc 22020ttcattcagc cgccgcactg tgcgcttacc tcctttgcca tgcttgatta gcaccggtgg 22080gttgctgaaa cccaccattt gtagcgccac atcttctctt tcttcctcgc tgtccacgat 22140tacctctggt gatggcgggc gctcgggctt gggagaaggg cgcttctttt tcttcttggg 22200cgcaatggcc aaatccgccg ccgaggtcga tggccgcggg ctgggtgtgc gcggcaccag 22260cgcgtcttgt gatgagtctt cctcgtcctc ggactcgata cgccgcctca tccgcttttt 22320tgggggcgcc cggggaggcg gcggcgacgg ggacggggac gacacgtcct ccatggttgg 22380gggacgtcgc gccgcaccgc gtccgcgctc gggggtggtt tcgcgctgct cctcttcccg 22440actggccatt tccttctcct ataggcagaa aaagatcatg gagtcagtcg agaagaagga 22500cagcctaacc gccccctctg agttcgccac caccgcctcc accgatgccg ccaacgcgcc 22560taccaccttc cccgtcgagg cacccccgct tgaggaggag gaagtgatta tcgagcagga 22620cccaggtttt gtaagcgaag acgacgagga ccgctcagta ccaacagagg ataaaaagca 22680agaccaggac aacgcagagg caaacgagga acaagtcggg cggggggacg aaaggcatgg 22740cgactaccta gatgtgggag acgacgtgct gttgaagcat ctgcagcgcc agtgcgccat 22800tatctgcgac gcgttgcaag agcgcagcga tgtgcccctc gccatagcgg atgtcagcct 22860tgcctacgaa cgccacctat tctcaccgcg cgtacccccc aaacgccaag aaaacggcac 22920atgcgagccc aacccgcgcc tcaacttcta ccccgtattt gccgtgccag aggtgcttgc 22980cacctatcac atctttttcc aaaactgcaa gataccccta tcctgccgtg ccaaccgcag 23040ccgagcggac aagcagctgg ccttgcggca gggcgctgtc atacctgata tcgcctcgct 23100caacgaagtg ccaaaaatct ttgagggtct tggacgcgac gagaagcgcg cggcaaacgc 23160tctgcaacag gaaaacagcg aaaatgaaag tcactctgga gtgttggtgg aactcgaggg 23220tgacaacgcg cgcctagccg tactaaaacg cagcatcgag gtcacccact ttgcctaccc 23280ggcacttaac ctacccccca aggtcatgag cacagtcatg agtgagctga tcgtgcgccg 23340tgcgcagccc ctggagaggg atgcaaattt gcaagaacaa acagaggagg gcctacccgc 23400agttggcgac gagcagctag cgcgctggct tcaaacgcgc gagcctgccg acttggagga 23460gcgacgcaaa ctaatgatgg ccgcagtgct cgttaccgtg gagcttgagt gcatgcagcg 23520gttctttgct gacccggaga tgcagcgcaa gctagaggaa acattgcact acacctttcg 23580acagggctac gtacgccagg cctgcaagat ctccaacgtg gagctctgca acctggtctc 23640ctaccttgga attttgcacg aaaaccgcct tgggcaaaac gtgcttcatt ccacgctcaa 23700gggcgaggcg cgccgcgact acgtccgcga ctgcgtttac ttatttctat gctacacctg 23760gcagacggcc atgggcgttt ggcagcagtg cttggaggag tgcaacctca aggagctgca 23820gaaactgcta aagcaaaact tgaaggacct atggacggcc ttcaacgagc gctccgtggc 23880cgcgcacctg gcggacatca ttttccccga acgcctgctt aaaaccctgc aacagggtct 23940gccagacttc accagtcaaa gcatgttgca gaactttagg aactttatcc tagagcgctc 24000aggaatcttg cccgccacct gctgtgcact tcctagcgac tttgtgccca ttaagtaccg 24060cgaatgccct ccgccgcttt ggggccactg ctaccttctg cagctagcca actaccttgc 24120ctaccactct gacataatgg aagacgtgag cggtgacggt ctactggagt gtcactgtcg 24180ctgcaaccta tgcaccccgc accgctccct ggtttgcaat tcgcagctgc ttaacgaaag 24240tcaaattatc ggtacctttg agctgcaggg tccctcgcct gacgaaaagt ccgcggctcc 24300ggggttgaaa ctcactccgg ggctgtggac gtcggcttac cttcgcaaat ttgtacctga 24360ggactaccac gcccacgaga ttaggttcta cgaagaccaa tcccgcccgc ctaatgcgga 24420gcttaccgcc tgcgtcatta cccagggcca cattcttggc caattgcaag ccatcaacaa 24480agcccgccaa gagtttctgc tacgaaaggg acggggggtt tacttggacc cccagtccgg 24540cgaggagctc aacccaatcc ccccgccgcc gcagccctat cagcagcagc cgcgggccct 24600tgcttcccag gatggcaccc aaaaagaagc tgcagctgcc gccgccaccc acggacgagg 24660aggaatactg ggacagtcag gcagaggagg ttttggacga ggaggaggag gacatgatgg 24720aagactggga gagcctagac gaggaagctt ccgaggtcga agaggtgtca gacgaaacac 24780cgtcaccctc ggtcgcattc ccctcgccgg cgccccagaa atcggcaacc ggttccagca 24840tggctacaac ctccgctcct caggcgccgc cggcactgcc cgttcgccga cccaaccgta 24900gatgggacac cactggaacc agggccggta agtccaagca gccgccgccg ttagcccaag 24960agcaacaaca gcgccaaggc taccgctcat ggcgcgggca caagaacgcc atagttgctt 25020gcttgcaaga ctgtgggggc aacatctcct tcgcccgccg ctttcttctc taccatcacg 25080gcgtggcctt cccccgtaac atcctgcatt actaccgtca tctctacagc ccatactgca 25140ccggcggcag cggcagcaac agcagcggcc acacagaagc aaaggcgacc ggatagcaag 25200actctgacaa agcccaagaa atccacagcg gcggcagcag caggaggagg agcgctgcgt 25260ctggcgccca acgaacccgt atcgacccgc gagcttagaa acaggatttt tcccactctg 25320tatgctatat ttcaacagag caggggccaa gaacaagagc tgaaaataaa aaacaggtct 25380ctgcgatccc tcacccgcag ctgcctgtat cacaaaagcg aagatcagct tcggcgcacg 25440ctggaagacg cggaggctct cttcagtaaa tactgcgcgc tgactcttaa ggactagttt 25500cgcgcccttt ctcaaattta agcgcgaaaa ctacgtcatc tccagcggcc acacccggcg 25560ccagcacctg ttgtcagcgc cattatgagc aaggaaattc ccacgcccta catgtggagt 25620taccagccac aaatgggact tgcggctgga gctgcccaag actactcaac ccgaataaac 25680tacatgagcg cgggacccca catgatatcc cgggtcaacg gaatacgcgc ccaccgaaac 25740cgaattctcc tggaacaggc ggctattacc accacacctc gtaataacct taatccccgt 25800agttggcccg ctgccctggt gtaccaggaa agtcccgctc ccaccactgt ggtacttccc 25860agagacgccc aggccgaagt tcagatgact aactcagggg cgcagcttgc gggcggcttt 25920cgtcacaggg tgcggtcgcc cgggcagggt ataactcacc tgacaatcag agggcgaggt 25980attcagctca acgacgagtc ggtgagctcc tcgcttggtc tccgtccgga cgggacattt 26040cagatcggcg gcgccggccg ctcttcattc acgcctcgtc aggcaatcct aactctgcag 26100acctcgtcct ctgagccgcg ctctggaggc attggaactc tgcaatttat tgaggagttt 26160gtgccatcgg tctactttaa ccccttctcg ggacctcccg gccactatcc ggatcaattt 26220attcctaact ttgacgcggt aaaggactcg gcggacggct acgactgaat gttaagtgga 26280gaggcagagc aactgcgcct gaaacacctg gtccactgtc gccgccacaa gtgctttgcc 26340cgcgactccg gtgagttttg ctactttgaa ttgcccgagg atcatatcga gggcccggcg 26400cacggcgtcc ggcttaccgc ccagggagag cttgcccgta gcctgattcg ggagtttacc 26460cagcgccccc tgctagttga gcgggacagg ggaccctgtg ttctcactgt gatttgcaac 26520tgtcctaacc ctggattaca tcaagatctt tgttgccatc tctgtgctga gtataataaa 26580tacagaaatt aaaatatact ggggctccta tcgccatcct gtaaacgcca ccgtcttcac 26640ccgcccaagc aaaccaaggc gaaccttacc tggtactttt aacatctctc cctctgtgat 26700ttacaacagt ttcaacccag acggagtgag tctacgagag aacctctccg agctcagcta 26760ctccatcaga aaaaacacca ccctccttac ctgccgggaa cgtacgagtg cgtcaccggc 26820cgctgcacca cacctaccgc ctgaccgtaa accagacttt ttccggacag acctcaataa 26880ctctgtttac cagaacagga ggtgagctta gaaaaccctt agggtattag gccaaaggcg 26940cagctactgt ggggtttatg aacaattcaa gcaactctac gggctattct aattcaggtt 27000tctctagaat cggggttggg gttattctct gtcttgtgat tctctttatt cttatactaa 27060cgcttctctg cctaaggctc gccgcctgct gtgtgcacat ttgcatttat tgtcagcttt 27120ttaaacgctg gggtcgccac ccaagatgat taggtacata atcctaggtt tactcaccct 27180tgcgtcagcc cacggtacca cccaaaaggt ggattttaag gagccagcct gtaatgttac 27240attcgcagct gaagctaatg agtgcaccac tcttataaaa tgcaccacag aacatgaaaa 27300gctgcttatt cgccacaaaa acaaaattgg caagtatgct gtttatgcta tttggcagcc 27360aggtgacact acagagtata atgttacagt tttccagggt aaaagtcata aaacttttat 27420gtatactttt ccattttatg aaatgtgcga cattaccatg tacatgagca aacagtataa 27480gttgtggccc ccacaaaatt gtgtggaaaa cactggcact ttctgctgca ctgctatgct 27540aattacagtg ctcgctttgg tctgtaccct actctatatt aaatacaaaa gcagacgcag 27600ctttattgag gaaaagaaaa tgccttaatt tactaagtta caaagctaat gtcaccacta 27660actgctttac tcgctgcttg caaaacaaat tcaaaaagtt agcattataa ttagaatagg 27720atttaaaccc cccggtcatt tcctgctcaa taccattccc ctgaacaatt gactctatgt 27780gggatatgct ccagcgctac aaccttgaag tcaggcttcc tggatgtcag catctgactt 27840tggccagcac ctgtcccgcg gatttgttcc agtccaacta cagcgaccca ccctaacaga 27900gatgaccaac acaaccaacg cggccgccgc taccggactt acatctacca caaatacacc 27960ccaagtttct gcctttgtca ataactggga taacttgggc atgtggtggt tctccatagc 28020gcttatgttt gtatgcctta ttattatgtg gctcatctgc tgcctaaagc gcaaacgcgc 28080ccgaccaccc atctatagtc ccatcattgt gctacaccca aacaatgatg gaatccatag 28140attggacgga ctgaaacaca tgttcttttc tcttacagta tgattaaatg agacatgatt 28200cctcgagttt ttatattact gacccttgtt gcgctttttt tgtgcgtgct ccacattggc 28260tgcggtttct cacatcgaag tagactgcat tccagccttc acagtctatt tgctttacgg 28320atttgtcacc ctcacgctca tctgcagcct catcactgtg gtcatcgcct ttatccagtg 28380cattgactgg gtctgtgtgc gctttgcata tctcagacac catccccagt acagggacag 28440gactatagct gagcttctta gaattcttta attatgaaat ttactgtgac ttttctgctg 28500attatttgca ccctatctgc gttttgttcc ccgacctcca agcctcaaag acatatatca 28560tgcagattca ctcgtatatg gaatattcca agttgctaca atgaaaaaag cgatctttcc 28620gaagcctggt tatatgcaat catctctgtt atggtgttct gcagtaccat cttagcccta 28680gctatatatc cctaccttga cattggctgg aacgcaatag atgccatgaa ccacccaact 28740ttccccgcgc ccgctatgct tccactgcaa caagttgttg ccggcggctt tgtcccagcc 28800aatcagcctc gcccaccttc tcccaccccc actgaaatca gctactttaa tctaacagga 28860ggagatgact gacaccctag atctagaaat ggacggaatt attacagagc agcgcctgct 28920agaaagacgc agggcagcgg ccgagcaaca gcgcatgaat caagagctcc aagacatggt 28980taacttgcac cagtgcaaaa ggggtatctt ttgtctggta aagcaggcca aagtcaccta 29040cgacagtaat accaccggac accgccttag ctacaagttg ccaaccaagc gtcagaaatt 29100ggtggtcatg gtgggagaaa agcccattac cataactcag cactcggtag aaaccgaagg 29160ctgcattcac tcaccttgtc aaggacctga ggatctctgc acccttatta agaccctgtg 29220cggtctcaaa gatcttattc cctttaacta ataaaaaaaa ataataaagc atcacttact 29280taaaatcagt tagcaaattt ctgtccagtt tattcagcag cacctccttg ccctcctccc 29340agctctggta ttgcagcttc ctcctggctg caaactttct ccacaatcta aatggaatgt 29400cagtttcctc ctgttcctgt ccatccgcac ccactatctt catgttgttg cagatgaagc 29460gcgcaagacc gtctgaagat accttcaacc ccgtgtatcc atatgacacg gaaaccggtc 29520ctccaactgt gccttttctt actcctccct ttgtatcccc caatgggttt caagagagtc 29580cccctggggt actctctttg cgcctatccg aacctctagt tacctccaat ggcatgcttg 29640cgctcaaaat gggcaacggc ctctctctgg acgaggccgg caaccttacc tcccaaaatg 29700taaccactgt gagcccacct ctcaaaaaaa ccaagtcaaa cataaacctg gaaatatctg 29760cacccctcac agttacctca gaagccctaa ctgtggctgc cgccgcacct ctaatggtcg 29820cgggcaacac actcaccatg caatcacagg ccccgctaac cgtgcacgac tccaaactta 29880gcattgccac ccaaggaccc ctcacagtgt cagaaggaaa gctagccctg caaacatcag 29940gccccctcac caccaccgat agcagtaccc ttactatcac tgcctcaccc cctctaacta 30000ctgccactgg tagcttgggc attgacttga aagagcccat ttatacacaa aatggaaaac

30060taggactaaa gtacggggct cctttgcatg taacagacga cctaaacact ttgaccgtag 30120caactggtcc aggtgtgact attaataata cttccttgca aactaaagtt actggagcct 30180tgggttttga ttcacaaggc aatatgcaac ttaatgtagc aggaggacta aggattgatt 30240ctcaaaacag acgccttata cttgatgtta gttatccgtt tgatgctcaa aaccaactaa 30300atctaagact aggacagggc cctcttttta taaactcagc ccacaacttg gatattaact 30360acaacaaagg cctttacttg tttacagctt caaacaattc caaaaagctt gaggttaacc 30420taagcactgc caaggggttg atgtttgacg ctacagccat agccattaat gcaggagatg 30480ggcttgaatt tggttcacct aatgcaccaa acacaaatcc cctcaaaaca aaaattggcc 30540atggcctaga atttgattca aacaaggcta tggttcctaa actaggaact ggccttagtt 30600ttgacagcac aggtgccatt acagtaggaa acaaaaataa tgataagcta actttgtgga 30660ccacaccagc tccatctcct aactgtagac taaatgcaga gaaagatgct aaactcactt 30720tggtcttaac aaaatgtggc agtcaaatac ttgctacagt ttcagttttg gctgttaaag 30780gcagtttggc tccaatatct ggaacagttc aaagtgctca tcttattata agatttgacg 30840aaaatggagt gctactaaac aattccttcc tggacccaga atattggaac tttagaaatg 30900gagatcttac tgaaggcaca gcctatacaa acgctgttgg atttatgcct aacctatcag 30960cttatccaaa atctcacggt aaaactgcca aaagtaacat tgtcagtcaa gtttacttaa 31020acggagacaa aactaaacct gtaacactaa ccattacact aaacggtaca caggaaacag 31080gagacacaac tccaagtgca tactctatgt cattttcatg ggactggtct ggccacaact 31140acattaatga aatatttgcc acatcctctt acactttttc atacattgcc caagaataaa 31200gaatcgtttg tgttatgttt caacgtgttt atttttcaat tgcagaaaat ttcaagtcat 31260ttttcattca gtagtatagc cccaccacca catagcttat acagatcacc gtaccttaat 31320caaactcaca gaaccctagt attcaacctg ccacctccct cccaacacac agagtacaca 31380gtcctttctc cccggctggc cttaaaaagc atcatatcat gggtaacaga catattctta 31440ggtgttatat tccacacggt ttcctgtcga gccaaacgct catcagtgat attaataaac 31500tccccgggca gctcacttaa gttcatgtcg ctgtccagct gctgagccac aggctgctgt 31560ccaacttgcg gttgcttaac gggcggcgaa ggagaagtcc acgcctacat gggggtagag 31620tcataatcgt gcatcaggat agggcggtgg tgctgcagca gcgcgcgaat aaactgctgc 31680cgccgccgct ccgtcctgca ggaatacaac atggcagtgg tctcctcagc gatgattcgc 31740accgcccgca gcataaggcg ccttgtcctc cgggcacagc agcgcaccct gatctcactt 31800aaatcagcac agtaactgca gcacagcacc acaatattgt tcaaaatccc acagtgcaag 31860gcgctgtatc caaagctcat ggcggggacc acagaaccca cgtggccatc ataccacaag 31920cgcaggtaga ttaagtggcg acccctcata aacacgctgg acataaacat tacctctttt 31980ggcatgttgt aattcaccac ctcccggtac catataaacc tctgattaaa catggcgcca 32040tccaccacca tcctaaacca gctggccaaa acctgcccgc cggctataca ctgcagggaa 32100ccgggactgg aacaatgaca gtggagagcc caggactcgt aaccatggat catcatgctc 32160gtcatgatat caatgttggc acaacacagg cacacgtgca tacacttcct caggattaca 32220agctcctccc gcgttagaac catatcccag ggaacaaccc attcctgaat cagcgtaaat 32280cccacactgc agggaagacc tcgcacgtaa ctcacgttgt gcattgtcaa agtgttacat 32340tcgggcagca gcggatgatc ctccagtatg gtagcgcggg tttctgtctc aaaaggaggt 32400agacgatccc tactgtacgg agtgcgccga gacaaccgag atcgtgttgg tcgtagtgtc 32460atgccaaatg gaacgccgga cgtagtcata tttcctgaag caaaaccagg tgcgggcgtg 32520acaaacagat ctgcgtctcc ggtctcgccg cttagatcgc tctgtgtagt agttgtagta 32580tatccactct ctcaaagcat ccaggcgccc cctggcttcg ggttctatgt aaactccttc 32640atgcgccgct gccctgataa catccaccac cgcagaataa gccacaccca gccaacctac 32700acattcgttc tgcgagtcac acacgggagg agcgggaaga gctggaagaa ccatgttttt 32760ttttttattc caaaagatta tccaaaacct caaaatgaag atctattaag tgaacgcgct 32820cccctccggt ggcgtggtca aactctacag ccaaagaaca gataatggca tttgtaagat 32880gttgcacaat ggcttccaaa aggcaaacgg ccctcacgtc caagtggacg taaaggctaa 32940acccttcagg gtgaatctcc tctataaaca ttccagcacc ttcaaccatg cccaaataat 33000tctcatctcg ccaccttctc aatatatctc taagcaaatc ccgaatatta agtccggcca 33060ttgtaaaaat ctgctccaga gcgccctcca ccttcagcct caagcagcga atcatgattg 33120caaaaattca ggttcctcac agacctgtat aagattcaaa agcggaacat taacaaaaat 33180accgcgatcc cgtaggtccc ttcgcagggc cagctgaaca taatcgtgca ggtctgcacg 33240gaccagcgcg gccacttccc cgccaggaac catgacaaaa gaacccacac tgattatgac 33300acgcatactc ggagctatgc taaccagcgt agccccgatg taagcttgtt gcatgggcgg 33360cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaa gcctcgcgca aaaaagaaag 33420cacatcgtag tcatgctcat gcagataaag gcaggtaagc tccggaacca ccacagaaaa 33480agacaccatt tttctctcaa acatgtctgc gggtttctgc ataaacacaa aataaaataa 33540caaaaaaaca tttaaacatt agaagcctgt cttacaacag gaaaaacaac ccttataagc 33600ataagacgga ctacggccat gccggcgtga ccgtaaaaaa actggtcacc gtgattaaaa 33660agcaccaccg acagctcctc ggtcatgtcc ggagtcataa tgtaagactc ggtaaacaca 33720tcaggttgat tcacatcggt cagtgctaaa aagcgaccga aatagcccgg gggaatacat 33780acccgcaggc gtagagacaa cattacagcc cccataggag gtataacaaa attaatagga 33840gagaaaaaca cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc accctcccgc 33900tccagaacaa catacagcgc ttccacagcg gcagccataa cagtcagcct taccagtaaa 33960aaagaaaacc tattaaaaaa acaccactcg acacggcacc agctcaatca gtcacagtgt 34020aaaaaagggc caagtgcaga gcgagtatat ataggactaa aaaatgacgt aacggttaaa 34080gtccacaaaa aacacccaga aaaccgcacg cgaacctacg cccagaaacg aaagccaaaa 34140aacccacaac ttcctcaaat cgtcacttcc gttttcccac gttacgtcac ttcccatttt 34200aagaaaacta caattcccaa cacatacaag ttactccgcc ctaaaaccta cgtcacccgc 34260cccgttccca cgccccgcgc cacgtcacaa actccacccc ctcattatca tattggcttc 34320aatccaaaat aaggtatatt attgatgatg 343502590DNAArtificial sequenceTNFR portion of the TNFR-Fas chimera (Fas-c) 2atgggcctct ccaccgtgcc tgacctgctg ctgccgctgg tgctcctgga gctgttggtg 60ggaatatacc cctcaggggt tattggactg gtccctcacc taggggacag ggagaagaga 120gatagtgtgt gtccccaagg aaaatatatc caccctcaaa ataattcgat ttgctgtacc 180aagtgccaca aaggaaccta cttgtacaat gactgtccag gcccggggca ggatacggac 240tgcagggagt gtgagagcgg ctccttcacc gcttcagaaa accacctcag acactgcctc 300agctgctcca aatgccgaaa ggaaatgggt caggtggaga tctcttcttg cacagtggac 360cgggacaccg tgtgtggctg caggaagaac cagtaccggc attattggag tgaaaacctt 420ttccagtgct tcaattgcag cctctgcctc aatgggaccg tgcacctctc ctgccaggag 480aaacagaaca ccgtgtgcac ctgccatgca ggtttctttc taagagaaaa cgagtgtgtc 540tcctgtagta actgtaagaa aagcctggag tgcacgaagt tgtgcctacc 5903511DNAArtificial sequenceFas portion of the TNFR-Fas chimera (Fas-c) 3aagcttagga tccagatcta acttggggtg gctttgtctt cttcttttgc caattccact 60aattgtttgg gtgaagagaa aggaagtaca gaaaacatgc agaaagcaca gaaaggaaaa 120ccaaggttct catgaatctc caaccttaaa tcctgaaaca gtggcaataa atttatctga 180tgttgacttg agtaaatata tcaccactat tgctggagtc atgacactaa gtcaagttaa 240aggctttgtt cgaaagaatg gtgtcaatga agccaaaata gatgagatca agaatgacaa 300tgtccaagac acagcagaac agaaagttca actgcttcgt aattggcatc aacttcatgg 360aaagaaagaa gcgtatgaca cattgattaa agatctcaaa aaagccaatc tttgtactct 420tgcagagaaa attcagacta tcatcctcaa ggacattact agtgactcag aaaattcaaa 480cttcagaaat gaaatccaaa gcttggtcta g 51141101DNAArtificial sequenceTNFR1-Fas chimera (Fas-c) coding sequence 4atgggcctct ccaccgtgcc tgacctgctg ctgccgctgg tgctcctgga gctgttggtg 60ggaatatacc cctcaggggt tattggactg gtccctcacc taggggacag ggagaagaga 120gatagtgtgt gtccccaagg aaaatatatc caccctcaaa ataattcgat ttgctgtacc 180aagtgccaca aaggaaccta cttgtacaat gactgtccag gcccggggca ggatacggac 240tgcagggagt gtgagagcgg ctccttcacc gcttcagaaa accacctcag acactgcctc 300agctgctcca aatgccgaaa ggaaatgggt caggtggaga tctcttcttg cacagtggac 360cgggacaccg tgtgtggctg caggaagaac cagtaccggc attattggag tgaaaacctt 420ttccagtgct tcaattgcag cctctgcctc aatgggaccg tgcacctctc ctgccaggag 480aaacagaaca ccgtgtgcac ctgccatgca ggtttctttc taagagaaaa cgagtgtgtc 540tcctgtagta actgtaagaa aagcctggag tgcacgaagt tgtgcctacc aagcttagga 600tccagatcta acttggggtg gctttgtctt cttcttttgc caattccact aattgtttgg 660gtgaagagaa aggaagtaca gaaaacatgc agaaagcaca gaaaggaaaa ccaaggttct 720catgaatctc caaccttaaa tcctgaaaca gtggcaataa atttatctga tgttgacttg 780agtaaatata tcaccactat tgctggagtc atgacactaa gtcaagttaa aggctttgtt 840cgaaagaatg gtgtcaatga agccaaaata gatgagatca agaatgacaa tgtccaagac 900acagcagaac agaaagttca actgcttcgt aattggcatc aacttcatgg aaagaaagaa 960gcgtatgaca cattgattaa agatctcaaa aaagccaatc tttgtactct tgcagagaaa 1020attcagacta tcatcctcaa ggacattact agtgactcag aaaattcaaa cttcagaaat 1080gaaatccaaa gcttggtcta g 110156DNAArtificial sequenceHypoxia responsive element - E-box 5gcacgt 6 644DNAArtificial sequenceMurine endothelial specific enhancer elemet 6gtacttcata cttttcattc caatggggtg actttgcttc tgga 447143DNAArtificial sequenceA triplicate copy of a murine enhancer sequence originated from the PPE-1 promoter 7gtacttcata cttttcattc caatggggtg actttgcttc tggagggtga ctttgcttct 60ggagccagta cttcatactt ttcattgtac ttcatacttt tcattccaat ggggtgactt 120tgcttctgga ggctagctgc cag 143847DNAArtificial sequenceEDC fragment 8ctggagggtg actttgcttc tggagccagt acttcatact tttcatt 47936460DNAArtificial sequencePPE-1-3X-FasC virl construct including repeat sequences 9catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420cgggtcaaag ttggcgtttt attattatag tcagtacgta cgtgtacttc tgatcggcga 480tactagggag ataaggatgt acctgacaaa accacattgt tgttgttatc attattattt 540agttttcctt ccttgctaac tcctgacgga atctttctca cctcaaatgc gaagtacttt 600agtttagaaa agacttggtg gaaggggtgg tggtggaaaa gtagggtgat cttccaaact 660aatctggttc cccgcccgcc ccagtagctg ggattcaaga gcgaagagtg gggatcgtcc 720ccttgtttga tcagaaagac ataaaaggaa aatcaagtga acaatgatca gccccacctc 780caccccaccc ccctgcgcgc gcacaataca atctatttaa ttgtacttca tacttttcat 840tccaatgggg tgactttgct tctggagaaa ctcttgattc ttgaactctg gggctggcag 900ctagcctcca gaagcaaagt caccccattg gaatgaaaag tatgaagtac aatgaaaagt 960atgaagtact ggctccagaa gcaaagtcac cctccagaag caaagtcacc ccattggaat 1020gaaaagtatg aagtacgcta gcaaaagggg aagcgggctg ctgctctctg caggttctgc 1080agcggtctct gtctagtggg tgttttcttt ttcttagccc tgcccctgga ttgtcagacg 1140gcgggcgtct gcctctgaag ttagccgtga tttcctctag agccgggtct tatctctggc 1200tgcacgttgc ctgtgggtga ctaatcacac aataacattg tttagggctg gaataaagtc 1260agagctgttt acccccactc tataggggtt caatataaaa aggcggcgga gaactgtccg 1320agtcagaagc gttcctgcac cggcgctgag agcctgaccc ggtctgctcc gctgtccttg 1380cgcgctgcct cccggctgcc cgcgacgctt tcgccccagt ggaagggcca cttgctgcgg 1440ccgctaattc tgcagatcgg gatccggcat gggcctctcc accgtgcctg acctgctgct 1500gccgctggtg ctcctggagc tgttggtggg aatatacccc tcaggggtta ttggactggt 1560ccctcaccta ggggacaggg agaagagaga tagtgtgtgt ccccaaggaa aatatatcca 1620ccctcaaaat aattcgattt gctgtaccaa gtgccacaaa ggaacctact tgtacaatga 1680ctgtccaggc ccggggcagg atacggactg cagggagtgt gagagcggct ccttcaccgc 1740ttcagaaaac cacctcagac actgcctcag ctgctccaaa tgccgaaagg aaatgggtca 1800ggtggagatc tcttcttgca cagtggaccg ggacaccgtg tgtggctgca ggaagaacca 1860gtaccggcat tattggagtg aaaacctttt ccagtgcttc aattgcagcc tctgcctcaa 1920tgggaccgtg cacctctcct gccaggagaa acagaacacc gtgtgcacct gccatgcagg 1980tttctttcta agagaaaacg agtgtgtctc ctgtagtaac tgtaagaaaa gcctggagtg 2040cacgaagttg tgcctaccaa gcttaggatc cagatctaac ttggggtggc tttgtcttct 2100tcttttgcca attccactaa ttgtttgggt gaagagaaag gaagtacaga aaacatgcag 2160aaagcacaga aaggaaaacc aaggttctca tgaatctcca accttaaatc ctgaaacagt 2220ggcaataaat ttatctgatg ttgacttgag taaatatatc accactattg ctggagtcat 2280gacactaagt caagttaaag gctttgttcg aaagaatggt gtcaatgaag ccaaaataga 2340tgagatcaag aatgacaatg tccaagacac agcagaacag aaagttcaac tgcttcgtaa 2400ttggcatcaa cttcatggaa agaaagaagc gtatgacaca ttgattaaag atctcaaaaa 2460agccaatctt tgtactcttg cagagaaaat tcagactatc atcctcaagg acattactag 2520tgactcagaa aattcaaact tcagaaatga aatccaaagc ttggtctagc tcgagcatgc 2580atctaggcgg ccgcatggca gaaattcgcg aattcgctag cgttaacgga tcctctagac 2640gagatccgaa cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa 2700atttcacaaa taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca 2760atgtatctta tcatgtctag atctgtactg aaatgtgtgg gcgtggctta agggtgggaa 2820agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 2880ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 2940ccccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 3000tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 3060cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 3120ctttcctgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 3180tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 3240agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 3300tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 3360gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 3420gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 3480gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 3540tgttgtagat gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca 3600gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 3660gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 3720tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 3780cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 3840cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 3900gggcggcggc ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga 3960tgagatcgtc ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa 4020tggttccatc cggcccaggg gcgtagttac cctcacagat ttaagggtgg gaaagaatat 4080ataaggtggg ggtcttatgt agttttgtat ctgttttgca gcagccgccg ccgccatgag 4140caccaactcg tttgatggaa gcattgtgag ctcatatttg acaacgcgca tgcccccatg 4200ggccggggtg cgtcagaatg tgatgggctc cagcattgat ggtcgccccg tcctgcccgc 4260aaactctact accttgacct acgagaccgt gtctggaacg ccgttggaga ctgcagcctc 4320cgccgccgct tcagccgctg cagccaccgc ccgcgggatt gtgactgact ttgctttcct 4380gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc cgcgatgaca agttgacggc 4440tcttttggca caattggatt ctttgacccg ggaacttaat gtcgtttctc agcagctgtt 4500ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc cctcccaatg cggtttaaaa 4560cataaataaa aaaccagact ctgtttggat ttggatcaag caagtgtctt gctgtcttta 4620tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg tctcggtcgt tgagggtcct 4680gtgtattttt tccaggacgt ggtaaaggtg actctggatg ttcagataca tgggcataag 4740cccgtctctg gggtggaggt agcaccactg cagagcttca tgctgcgggg tggtgttgta 4800gatgatccag tcgtagcagg agcgctgggc gtggtgccta aaaatgtctt tcagtagcaa 4860gctgattgcc aggggcaggc ccttggtgta agtgtttaca aagcggttaa gctgggatgg 4920gtgcatacgt ggggatatga gatgcatctt ggactgtatt tttaggttgg ctatgttccc 4980agccatatcc ctccggggat tcatgttgtg cagaaccacc agcacagtgt atccggtgca 5040cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg aagaacttgg agacgccctt 5100gtgacctcca agattttcca tgcattcgtc cataatgatg gcaatgggcc cacgggcggc 5160ggcctgggcg aagatatttc tgggatcact aacgtcatag ttgtgttcca ggatgagatc 5220gtcataggcc atttttacaa agcgcgggcg gagggtgcca gactgcggta taatggttcc 5280atccggccca ggggcgtagt taccctcaca gatttgcatt tcccacgctt tgagttcaga 5340tggggggatc atgtctacct gcggggcgat gaagaaaacg gtttccgggg taggggagat 5400cagctgggaa gaaagcaggt tcctgagcag ctgcgactta ccgcagccgg tgggcccgta 5460aatcacacct attaccggct gcaactggta gttaagagag ctgcagctgc cgtcatccct 5520gagcaggggg gccacttcgt taagcatgtc cctgactcgc atgttttccc tgaccaaatc 5580cgccagaagg cgctcgccgc ccagcgatag cagttcttgc aaggaagcaa agtttttcaa 5640cggtttgaga ccgtccgccg taggcatgct tttgagcgtt tgaccaagca gttccaggcg 5700gtcccacagc tcggtcacct gctctacggc atctcgatcc agcatatctc ctcgtttcgc 5760gggttggggc ggctttcgct gtacggcagt agtcggtgct cgtccagacg ggccagggtc 5820atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct gggtcacggt gaaggggtgc 5880gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg tcctgctggt gctgaagcgc 5940tgccggtctt cgccctgcgc gtcggccagg tagcatttga ccatggtgtc atagtccagc 6000ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg aggaggcgcc gcacgagggg 6060cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa ataccgattc cggggagtag 6120gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca cgagccaggt gagctctggc 6180cgttcggggt caaaaaccag gtttccccca tgctttttga tgcgtttctt acctctggtt 6240tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt ccgtgtcccc gtatacagac 6300ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct cgtatagaaa ctcggaccac 6360tctgagacaa aggctcgcgt ccaggccagc acgaaggagg ctaagtggga ggggtagcgg 6420tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa gacacatgtc gccctcttcg 6480gcatcaagga aggtgattgg tttgtaggtg taggccacgt gaccgggtgt tcctgaaggg 6540gggctataaa agggggtggg ggcgcgttcg tcctcactct cttccgcatc gctgtctgcg 6600agggccagct gttggggtga gtactccctc tgaaaagcgg gcatgacttc tgcgctaaga 6660ttgtcagttt ccaaaaacga ggaggatttg atattcacct ggcccgcggt gatgcctttg 6720agggtggccg catccatctg gtcagaaaag acaatctttt tgttgtcaag cttggtggca 6780aacgacccgt agagggcgtt ggacagcaac ttggcgatgg agcgcagggt ttggtttttg 6840tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca cgtattcgcg cgcaacgcac 6900cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca ggtgcacgcg ccaaccgcgg 6960ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc cgcgtaggcg ctcgttggtc 7020cagcagaggc ggccgccctt gcgcgagcag aatggcggta gggggtctag ctgcgtctcg 7080tccggggggt ctgcgtccac ggtaaagacc ccgggcagca ggcgcgcgtc gaagtagtct 7140atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc gggcggcaag cgcgcgctcg 7200tatgggttga gtgggggacc ccatggcatg gggtgggtga gcgcggaggc gtacatgccg 7260caaatgtcgt aaacgtagag gggctctctg agtattccaa gatatgtagg gtagcatctt 7320ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt gcgagggagc gaggaggtcg 7380ggaccgaggt tgctacgggc gggctgctct gctcggaaga ctatctgcct gaagatggca 7440tgtgagttgg atgatatggt tggacgctgg aagacgttga agctggcgtc tgtgagacct 7500accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct tgttgaccag ctcggcggtg 7560acctgcacgt ctagggcgca

gtagtccagg gtttccttga tgatgtcata cttatcctgt 7620cccttttttt tccacagctc gcggttgagg acaaactctt cgcggtcttt ccagtactct 7680tggatcggaa acccgtcggc ctccgaacgg taagagccta gcatgtagaa ctggttgacg 7740gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt atgcctgcgc ggccttccgg 7800agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga ctttgaggta ctggtatttg 7860aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa agtccgtgcg ctttttggaa 7920cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta tctttcccgc gcgaggcata 7980aagttgcgtg tgatgcggaa gggtcccggc acctcggaac ggttgttaat tacctgggcg 8040gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca caatgtaaag ttccaagaag 8100cgcgggatgc ccttgatgga aggcaatttt ttaagttcct cgtaggtgag ctcttcaggg 8160gagctgagcc cgtgctctga aagggcccag tctgcaagat gagggttgga agcgacgaat 8220gagctccaca ggtcacgggc cattagcatt tgcaggtggt cgcgaaaggt cctaaactgg 8280cgacctatgg ccattttttc tggggtgatg cagtagaagg taagcgggtc ttgttcccag 8340cggtcccatc caaggttcgc ggctaggtct cgcgcggcag tcactagagg ctcatctccg 8400ccgaacttca tgaccagcat gaagggcacg agctgcttcc caaaggcccc catccaagta 8460taggtctcta catcgtaggt gacaaagaga cgctcggtgc gaggatgcga gccgatcggg 8520aagaactgga tctcccgcca ccaattggag gagtggctat tgatgtggtg aaagtagaag 8580tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa aacgtgcgca gtactggcag 8640cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac gaccgcgcac aaggaagcag 8700agtgggaatt tgagcccctc gcctggcggg tttggctggt ggtcttctac ttcggctgct 8760tgtccttgac cgtctggctg ctcgagggga gttacggtgg atcggaccac cacgccgcgc 8820gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct tgatgacaac atcgcgcaga 8880tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt caggcgggag ctcctgcagg 8940tttacctcgc atagacgggt cagggcgcgg gctagatcca ggtgatacct aatttccagg 9000ggctggttgg tggcggcgtc gatggcttgc aagaggccgc atccccgcgg cgcgactacg 9060gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg atgatgcatc taaaagcggt 9120gacgcgggcg agcccccgga ggtagggggg gctccggacc cgccgggaga gggggcaggg 9180gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc gcgtaggttg ctggcgaacg 9240cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg cgtgaagacg acgggcccgg 9300tgagcttgaa cctgaaagag agttcgacag aatcaatttc ggtgtcgttg acggcggcct 9360ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata ggcgatctcg gccatgaact 9420gctcgatctc ttcctcctgg agatctccgc gtccggctcg ctccacggtg gcggcgaggt 9480cgttggaaat gcgggccatg agctgcgaga aggcgttgag gcctccctcg ttccagacgc 9540ggctgtagac cacgccccct tcggcatcgc gggcgcgcat gaccacctgc gcgagattga 9600gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg ctgaaagagg tagttgaggg 9660tggtggcggt gtgttctgcc acgaagaagt acataaccca gcgtcgcaac gtggattcgt 9720tgatatcccc caaggcctca aggcgctcca tggcctcgta gaagtccacg gcgaagttga 9780aaaactggga gttgcgcgcc gacacggtta actcctcctc cagaagacgg atgagctcgg 9840cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc ctcttcttct tcttcaatct 9900cctcttccat aagggcctcc ccttcttctt cttctggcgg cggtggggga ggggggacac 9960ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg ctcgatcatc tccccgcggc 10020gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg ggggcgcagt tggaagacgc 10080cgcccgtcat gtcccggtta tgggttggcg gggggctgcc atgcggcagg gatacggcgc 10140taacgatgca tctcaacaat tgttgtgtag gtactccgcc gccgagggac ctgagcgagt 10200ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc taaccagtca cagtcgcaag 10260gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc ggggttgttt ctggcggagg 10320tgctgctgat gatgtaatta aagtaggcgg tcttgagacg gcggatggtc gacagaagca 10380ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc ggccatgccc caggcttcgt 10440tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag cctttctacc ggcacttctt 10500cttctccttc ctcttgtcct gcatctcttg catctatcgc tgcggcggcg gcggagtttg 10560gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc gaagcccctc atcggctgaa 10620gcagggctag gtcggcgaca acgcgctcgg ctaatatggc ctgctgcacc tgcgtgaggg 10680tagactggaa gtcatccatg tccacaaagc ggtggtatgc gcccgtgttg atggtgtaag 10740tgcagttggc cataacggac cagttaacgg tctggtgacc cggctgcgag agctcggtgt 10800acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc gttgcaagtc cgcaccaggt 10860actggtatcc caccaaaaag tgcggcggcg gctggcggta gaggggccag cgtagggtgg 10920ccggggctcc gggggcgaga tcttccaaca taaggcgatg atatccgtag atgtacctgg 10980acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg aaagtcgcgg acgcggttcc 11040agatgttgcg cagcggcaaa aagtgctcca tggtcgggac gctctggccg gtcaggcgcg 11100cgcaatcgtt gacgctctag accgtgcaaa aggagagcct gtaagcgggc actcttccgt 11160ggtctggtgg ataaattcgc aagggtatca tggcggacga ccggggttcg agccccgtat 11220ccggccgtcc gccgtgatcc atgcggttac cgcccgcgtg tcgaacccag gtgtgcgacg 11280tcagacaacg ggggagtgct ccttttggct tccttccagg cgcggcggct gctgcgctag 11340cttttttggc cactggccgc gcgcagcgta agcggttagg ctggaaagcg aaagcattaa 11400gtggctcgct ccctgtagcc ggagggttat tttccaaggg ttgagtcgcg ggacccccgg 11460ttcgagtctc ggaccggccg gactgcggcg aacgggggtt tgcctccccg tcatgcaaga 11520ccccgcttgc aaattcctcc ggaaacaggg acgagcccct tttttgcttt tcccagatgc 11580atccggtgct gcggcagatg cgcccccctc ctcagcagcg gcaagagcaa gagcagcggc 11640agacatgcag ggcaccctcc cctcctccta ccgcgtcagg aggggcgaca tccgcggttg 11700acgcggcagc agatggtgat tacgaacccc cgcggcgccg ggcccggcac tacctggact 11760tggaggaggg cgagggcctg gcgcggctag gagcgccctc tcctgagcgg cacccaaggg 11820tgcagctgaa gcgtgatacg cgtgaggcgt acgtgccgcg gcagaacctg tttcgcgacc 11880gcgagggaga ggagcccgag gagatgcggg atcgaaagtt ccacgcaggg cgcgagctgc 11940ggcatggcct gaatcgcgag cggttgctgc gcgaggagga ctttgagccc gacgcgcgaa 12000ccgggattag tcccgcgcgc gcacacgtgg cggccgccga cctggtaacc gcatacgagc 12060agacggtgaa ccaggagatt aactttcaaa aaagctttaa caaccacgtg cgtacgcttg 12120tggcgcgcga ggaggtggct ataggactga tgcatctgtg ggactttgta agcgcgctgg 12180agcaaaaccc aaatagcaag ccgctcatgg cgcagctgtt ccttatagtg cagcacagca 12240gggacaacga ggcattcagg gatgcgctgc taaacatagt agagcccgag ggccgctggc 12300tgctcgattt gataaacatc ctgcagagca tagtggtgca ggagcgcagc ttgagcctgg 12360ctgacaaggt ggccgccatc aactattcca tgcttagcct gggcaagttt tacgcccgca 12420agatatacca taccccttac gttcccatag acaaggaggt aaagatcgag gggttctaca 12480tgcgcatggc gctgaaggtg cttaccttga gcgacgacct gggcgtttat cgcaacgagc 12540gcatccacaa ggccgtgagc gtgagccggc ggcgcgagct cagcgaccgc gagctgatgc 12600acagcctgca aagggccctg gctggcacgg gcagcggcga tagagaggcc gagtcctact 12660ttgacgcggg cgctgacctg cgctgggccc caagccgacg cgccctggag gcagctgggg 12720ccggacctgg gctggcggtg gcacccgcgc gcgctggcaa cgtcggcggc gtggaggaat 12780atgacgagga cgatgagtac gagccagagg acggcgagta ctaagcggtg atgtttctga 12840tcagatgatg caagacgcaa cggacccggc ggtgcgggcg gcgctgcaga gccagccgtc 12900cggccttaac tccacggacg actggcgcca ggtcatggac cgcatcatgt cgctgactgc 12960gcgcaatcct gacgcgttcc ggcagcagcc gcaggccaac cggctctccg caattctgga 13020agcggtggtc ccggcgcgcg caaaccccac gcacgagaag gtgctggcga tcgtaaacgc 13080gctggccgaa aacagggcca tccggcccga cgaggccggc ctggtctacg acgcgctgct 13140tcagcgcgtg gctcgttaca acagcggcaa cgtgcagacc aacctggacc ggctggtggg 13200ggatgtgcgc gaggccgtgg cgcagcgtga gcgcgcgcag cagcagggca acctgggctc 13260catggttgca ctaaacgcct tcctgagtac acagcccgcc aacgtgccgc ggggacagga 13320ggactacacc aactttgtga gcgcactgcg gctaatggtg actgagacac cgcaaagtga 13380ggtgtaccag tctgggccag actatttttt ccagaccagt agacaaggcc tgcagaccgt 13440aaacctgagc caggctttca aaaacttgca ggggctgtgg ggggtgcggg ctcccacagg 13500cgaccgcgcg accgtgtcta gcttgctgac gcccaactcg cgcctgttgc tgctgctaat 13560agcgcccttc acggacagtg gcagcgtgtc ccgggacaca tacctaggtc acttgctgac 13620actgtaccgc gaggccatag gtcaggcgca tgtggacgag catactttcc aggagattac 13680aagtgtcagc cgcgcgctgg ggcaggagga cacgggcagc ctggaggcaa ccctaaacta 13740cctgctgacc aaccggcggc agaagatccc ctcgttgcac agtttaaaca gcgaggagga 13800gcgcattttg cgctacgtgc agcagagcgt gagccttaac ctgatgcgcg acggggtaac 13860gcccagcgtg gcgctggaca tgaccgcgcg caacatggaa ccgggcatgt atgcctcaaa 13920ccggccgttt atcaaccgcc taatggacta cttgcatcgc gcggccgccg tgaaccccga 13980gtatttcacc aatgccatct tgaacccgca ctggctaccg ccccctggtt tctacaccgg 14040gggattcgag gtgcccgagg gtaacgatgg attcctctgg gacgacatag acgacagcgt 14100gttttccccg caaccgcaga ccctgctaga gttgcaacag cgcgagcagg cagaggcggc 14160gctgcgaaag gaaagcttcc gcaggccaag cagcttgtcc gatctaggcg ctgcggcccc 14220gcggtcagat gctagtagcc catttccaag cttgataggg tctcttacca gcactcgcac 14280cacccgcccg cgcctgctgg gcgaggagga gtacctaaac aactcgctgc tgcagccgca 14340gcgcgaaaaa aacctgcctc cggcatttcc caacaacggg atagagagcc tagtggacaa 14400gatgagtaga tggaagacgt acgcgcagga gcacagggac gtgccaggcc cgcgcccgcc 14460cacccgtcgt caaaggcacg accgtcagcg gggtctggtg tgggaggacg atgactcggc 14520agacgacagc agcgtcctgg atttgggagg gagtggcaac ccgtttgcgc accttcgccc 14580caggctgggg agaatgtttt aaaaaaaaaa aaagcatgat gcaaaataaa aaactcacca 14640aggccatggc accgagcgtt ggttttcttg tattcccctt agtatgcggc gcgcggcgat 14700gtatgaggaa ggtcctcctc cctcctacga gagtgtggtg agcgcggcgc cagtggcggc 14760ggcgctgggt tctcccttcg atgctcccct ggacccgccg tttgtgcctc cgcggtacct 14820gcggcctacc ggggggagaa acagcatccg ttactctgag ttggcacccc tattcgacac 14880cacccgtgtg tacctggtgg acaacaagtc aacggatgtg gcatccctga actaccagaa 14940cgaccacagc aactttctga ccacggtcat tcaaaacaat gactacagcc cgggggaggc 15000aagcacacag accatcaatc ttgacgaccg gtcgcactgg ggcggcgacc tgaaaaccat 15060cctgcatacc aacatgccaa atgtgaacga gttcatgttt accaataagt ttaaggcgcg 15120ggtgatggtg tcgcgcttgc ctactaagga caatcaggtg gagctgaaat acgagtgggt 15180ggagttcacg ctgcccgagg gcaactactc cgagaccatg accatagacc ttatgaacaa 15240cgcgatcgtg gagcactact tgaaagtggg cagacagaac ggggttctgg aaagcgacat 15300cggggtaaag tttgacaccc gcaacttcag actggggttt gaccccgtca ctggtcttgt 15360catgcctggg gtatatacaa acgaagcctt ccatccagac atcattttgc tgccaggatg 15420cggggtggac ttcacccaca gccgcctgag caacttgttg ggcatccgca agcggcaacc 15480cttccaggag ggctttagga tcacctacga tgatctggag ggtggtaaca ttcccgcact 15540gttggatgtg gacgcctacc aggcgagctt gaaagatgac accgaacagg gcgggggtgg 15600cgcaggcggc agcaacagca gtggcagcgg cgcggaagag aactccaacg cggcagccgc 15660ggcaatgcag ccggtggagg acatgaacga tcatgccatt cgcggcgaca cctttgccac 15720acgggctgag gagaagcgcg ctgaggccga agcagcggcc gaagctgccg cccccgctgc 15780gcaacccgag gtcgagaagc ctcagaagaa accggtgatc aaacccctga cagaggacag 15840caagaaacgc agttacaacc taataagcaa tgacagcacc ttcacccagt accgcagctg 15900gtaccttgca tacaactacg gcgaccctca gaccggaatc cgctcatgga ccctgctttg 15960cactcctgac gtaacctgcg gctcggagca ggtctactgg tcgttgccag acatgatgca 16020agaccccgtg accttccgct ccacgcgcca gatcagcaac tttccggtgg tgggcgccga 16080gctgttgccc gtgcactcca agagcttcta caacgaccag gccgtctact cccaactcat 16140ccgccagttt acctctctga cccacgtgtt caatcgcttt cccgagaacc agattttggc 16200gcgcccgcca gcccccacca tcaccaccgt cagtgaaaac gttcctgctc tcacagatca 16260cgggacgcta ccgctgcgca acagcatcgg aggagtccag cgagtgacca ttactgacgc 16320cagacgccgc acctgcccct acgtttacaa ggccctgggc atagtctcgc cgcgcgtcct 16380atcgagccgc actttttgag caagcatgtc catccttata tcgcccagca ataacacagg 16440ctggggcctg cgcttcccaa gcaagatgtt tggcggggcc aagaagcgct ccgaccaaca 16500cccagtgcgc gtgcgcgggc actaccgcgc gccctggggc gcgcacaaac gcggccgcac 16560tgggcgcacc accgtcgatg acgccatcga cgcggtggtg gaggaggcgc gcaactacac 16620gcccacgccg ccaccagtgt ccacagtgga cgcggccatt cagaccgtgg tgcgcggagc 16680ccggcgctat gctaaaatga agagacggcg gaggcgcgta gcacgtcgcc accgccgccg 16740acccggcact gccgcccaac gcgcggcggc ggccctgctt aaccgcgcac gtcgcaccgg 16800ccgacgggcg gccatgcggg ccgctcgaag gctggccgcg ggtattgtca ctgtgccccc 16860caggtccagg cgacgagcgg ccgccgcagc agccgcggcc attagtgcta tgactcaggg 16920tcgcaggggc aacgtgtatt gggtgcgcga ctcggttagc ggcctgcgcg tgcccgtgcg 16980cacccgcccc ccgcgcaact agattgcaag aaaaaactac ttagactcgt actgttgtat 17040gtatccagcg gcggcggcgc gcaacgaagc tatgtccaag cgcaaaatca aagaagagat 17100gctccaggtc atcgcgccgg agatctatgg ccccccgaag aaggaagagc aggattacaa 17160gccccgaaag ctaaagcggg tcaaaaagaa aaagaaagat gatgatgatg aacttgacga 17220cgaggtggaa ctgctgcacg ctaccgcgcc caggcgacgg gtacagtgga aaggtcgacg 17280cgtaaaacgt gttttgcgac ccggcaccac cgtagtcttt acgcccggtg agcgctccac 17340ccgcacctac aagcgcgtgt atgatgaggt gtacggcgac gaggacctgc ttgagcaggc 17400caacgagcgc ctcggggagt ttgcctacgg aaagcggcat aaggacatgc tggcgttgcc 17460gctggacgag ggcaacccaa cacctagcct aaagcccgta acactgcagc aggtgctgcc 17520cgcgcttgca ccgtccgaag aaaagcgcgg cctaaagcgc gagtctggtg acttggcacc 17580caccgtgcag ctgatggtac ccaagcgcca gcgactggaa gatgtcttgg aaaaaatgac 17640cgtggaacct gggctggagc ccgaggtccg cgtgcggcca atcaagcagg tggcgccggg 17700actgggcgtg cagaccgtgg acgttcagat acccactacc agtagcacca gtattgccac 17760cgccacagag ggcatggaga cacaaacgtc cccggttgcc tcagcggtgg cggatgccgc 17820ggtgcaggcg gtcgctgcgg ccgcgtccaa gacctctacg gaggtgcaaa cggacccgtg 17880gatgtttcgc gtttcagccc cccggcgccc gcgccgttcg aggaagtacg gcgccgccag 17940cgcgctactg cccgaatatg ccctacatcc ttccattgcg cctacccccg gctatcgtgg 18000ctacacctac cgccccagaa gacgagcaac tacccgacgc cgaaccacca ctggaacccg 18060ccgccgccgt cgccgtcgcc agcccgtgct ggccccgatt tccgtgcgca gggtggctcg 18120cgaaggaggc aggaccctgg tgctgccaac agcgcgctac caccccagca tcgtttaaaa 18180gccggtcttt gtggttcttg cagatatggc cctcacctgc cgcctccgtt tcccggtgcc 18240gggattccga ggaagaatgc accgtaggag gggcatggcc ggccacggcc tgacgggcgg 18300catgcgtcgt gcgcaccacc ggcggcggcg cgcgtcgcac cgtcgcatgc gcggcggtat 18360cctgcccctc cttattccac tgatcgccgc ggcgattggc gccgtgcccg gaattgcatc 18420cgtggccttg caggcgcaga gacactgatt aaaaacaagt tgcatgtgga aaaatcaaaa 18480taaaaagtct ggactctcac gctcgcttgg tcctgtaact attttgtaga atggaagaca 18540tcaactttgc gtctctggcc ccgcgacacg gctcgcgccc gttcatggga aactggcaag 18600atatcggcac cagcaatatg agcggtggcg ccttcagctg gggctcgctg tggagcggca 18660ttaaaaattt cggttccacc gttaagaact atggcagcaa ggcctggaac agcagcacag 18720gccagatgct gagggataag ttgaaagagc aaaatttcca acaaaaggtg gtagatggcc 18780tggcctctgg cattagcggg gtggtggacc tggccaacca ggcagtgcaa aataagatta 18840acagtaagct tgatccccgc cctcccgtag aggagcctcc accggccgtg gagacagtgt 18900ctccagaggg gcgtggcgaa aagcgtccgc gccccgacag ggaagaaact ctggtgacgc 18960aaatagacga gcctccctcg tacgaggagg cactaaagca aggcctgccc accacccgtc 19020ccatcgcgcc catggctacc ggagtgctgg gccagcacac acccgtaacg ctggacctgc 19080ctccccccgc cgacacccag cagaaacctg tgctgccagg cccgaccgcc gttgttgtaa 19140cccgtcctag ccgcgcgtcc ctgcgccgcg ccgccagcgg tccgcgatcg ttgcggcccg 19200tagccagtgg caactggcaa agcacactga acagcatcgt gggtctgggg gtgcaatccc 19260tgaagcgccg acgatgcttc tgatagctaa cgtgtcgtat gtgtgtcatg tatgcgtcca 19320tgtcgccgcc agaggagctg ctgagccgcc gcgcgcccgc tttccaagat ggctacccct 19380tcgatgatgc cgcagtggtc ttacatgcac atctcgggcc aggacgcctc ggagtacctg 19440agccccgggc tggtgcagtt tgcccgcgcc accgagacgt acttcagcct gaataacaag 19500tttagaaacc ccacggtggc gcctacgcac gacgtgacca cagaccggtc ccagcgtttg 19560acgctgcggt tcatccctgt ggaccgtgag gatactgcgt actcgtacaa ggcgcggttc 19620accctagctg tgggtgataa ccgtgtgctg gacatggctt ccacgtactt tgacatccgc 19680ggcgtgctgg acaggggccc tacttttaag ccctactctg gcactgccta caacgccctg 19740gctcccaagg gtgccccaaa tccttgcgaa tgggatgaag ctgctactgc tcttgaaata 19800aacctagaag aagaggacga tgacaacgaa gacgaagtag acgagcaagc tgagcagcaa 19860aaaactcacg tatttgggca ggcgccttat tctggtataa atattacaaa ggagggtatt 19920caaataggtg tcgaaggtca aacacctaaa tatgccgata aaacatttca acctgaacct 19980caaataggag aatctcagtg gtacgaaaca gaaattaatc atgcagctgg gagagtccta 20040aaaaagacta ccccaatgaa accatgttac ggttcatatg caaaacccac aaatgaaaat 20100ggagggcaag gcattcttgt aaagcaacaa aatggaaagc tagaaagtca agtggaaatg 20160caatttttct caactactga ggcagccgca ggcaatggtg ataacttgac tcctaaagtg 20220gtattgtaca gtgaagatgt agatatagaa accccagaca ctcatatttc ttacatgccc 20280actattaagg aaggtaactc acgagaacta atgggccaac aatctatgcc caacaggcct 20340aattacattg cttttaggga caattttatt ggtctaatgt attacaacag cacgggtaat 20400atgggtgttc tggcgggcca agcatcgcag ttgaatgctg ttgtagattt gcaagacaga 20460aacacagagc tttcatacca gcttttgctt gattccattg gtgatagaac caggtacttt 20520tctatgtgga atcaggctgt tgacagctat gatccagatg ttagaattat tgaaaatcat 20580ggaactgaag atgaacttcc aaattactgc tttccactgg gaggtgtgat taatacagag 20640actcttacca aggtaaaacc taaaacaggt caggaaaatg gatgggaaaa agatgctaca 20700gaattttcag ataaaaatga aataagagtt ggaaataatt ttgccatgga aatcaatcta 20760aatgccaacc tgtggagaaa tttcctgtac tccaacatag cgctgtattt gcccgacaag 20820ctaaagtaca gtccttccaa cgtaaaaatt tctgataacc caaacaccta cgactacatg 20880aacaagcgag tggtggctcc cgggctagtg gactgctaca ttaaccttgg agcacgctgg 20940tcccttgact atatggacaa cgtcaaccca tttaaccacc accgcaatgc tggcctgcgc 21000taccgctcaa tgttgctggg caatggtcgc tatgtgccct tccacatcca ggtgcctcag 21060aagttctttg ccattaaaaa cctccttctc ctgccgggct catacaccta cgagtggaac 21120ttcaggaagg atgttaacat ggttctgcag agctccctag gaaatgacct aagggttgac 21180ggagccagca ttaagtttga tagcatttgc ctttacgcca ccttcttccc catggcccac 21240aacaccgcct ccacgcttga ggccatgctt agaaacgaca ccaacgacca gtcctttaac 21300gactatctct ccgccgccaa catgctctac cctatacccg ccaacgctac caacgtgccc 21360atatccatcc cctcccgcaa ctgggcggct ttccgcggct gggccttcac gcgccttaag 21420actaaggaaa ccccatcact gggctcgggc tacgaccctt attacaccta ctctggctct 21480ataccctacc tagatggaac cttttacctc aaccacacct ttaagaaggt ggccattacc 21540tttgactctt ctgtcagctg gcctggcaat gaccgcctgc ttacccccaa cgagtttgaa 21600attaagcgct cagttgacgg ggagggttac aacgttgccc agtgtaacat gaccaaagac 21660tggttcctgg tacaaatgct agctaactat aacattggct accagggctt ctatatccca 21720gagagctaca aggaccgcat gtactccttc tttagaaact tccagcccat gagccgtcag 21780gtggtggatg atactaaata caaggactac caacaggtgg gcatcctaca ccaacacaac 21840aactctggat ttgttggcta ccttgccccc accatgcgcg aaggacaggc ctaccctgct 21900aacttcccct atccgcttat aggcaagacc gcagttgaca gcattaccca gaaaaagttt 21960ctttgcgatc gcaccctttg gcgcatccca ttctccagta actttatgtc catgggcgca 22020ctcacagacc tgggccaaaa ccttctctac gccaactccg cccacgcgct agacatgact 22080tttgaggtgg atcccatgga cgagcccacc cttctttatg ttttgtttga agtctttgac 22140gtggtccgtg tgcaccagcc gcaccgcggc gtcatcgaaa ccgtgtacct gcgcacgccc 22200ttctcggccg gcaacgccac aacataaaga agcaagcaac atcaacaaca gctgccgcca 22260tgggctccag tgagcaggaa ctgaaagcca ttgtcaaaga tcttggttgt gggccatatt 22320ttttgggcac ctatgacaag cgctttccag gctttgtttc tccacacaag ctcgcctgcg 22380ccatagtcaa tacggccggt cgcgagactg ggggcgtaca ctggatggcc tttgcctgga 22440acccgcactc aaaaacatgc tacctctttg agccctttgg cttttctgac cagcgactca 22500agcaggttta ccagtttgag tacgagtcac tcctgcgccg tagcgccatt gcttcttccc 22560ccgaccgctg tataacgctg gaaaagtcca cccaaagcgt acaggggccc aactcggccg 22620cctgtggact attctgctgc

atgtttctcc acgcctttgc caactggccc caaactccca 22680tggatcacaa ccccaccatg aaccttatta ccggggtacc caactccatg ctcaacagtc 22740cccaggtaca gcccaccctg cgtcgcaacc aggaacagct ctacagcttc ctggagcgcc 22800actcgcccta cttccgcagc cacagtgcgc agattaggag cgccacttct ttttgtcact 22860tgaaaaacat gtaaaaataa tgtactagag acactttcaa taaaggcaaa tgcttttatt 22920tgtacactct cgggtgatta tttaccccca cccttgccgt ctgcgccgtt taaaaatcaa 22980aggggttctg ccgcgcatcg ctatgcgcca ctggcaggga cacgttgcga tactggtgtt 23040tagtgctcca cttaaactca ggcacaacca tccgcggcag ctcggtgaag ttttcactcc 23100acaggctgcg caccatcacc aacgcgttta gcaggtcggg cgccgatatc ttgaagtcgc 23160agttggggcc tccgccctgc gcgcgcgagt tgcgatacac agggttgcag cactggaaca 23220ctatcagcgc cgggtggtgc acgctggcca gcacgctctt gtcggagatc agatccgcgt 23280ccaggtcctc cgcgttgctc agggcgaacg gagtcaactt tggtagctgc cttcccaaaa 23340agggcgcgtg cccaggcttt gagttgcact cgcaccgtag tggcatcaaa aggtgaccgt 23400gcccggtctg ggcgttagga tacagcgcct gcataaaagc cttgatctgc ttaaaagcca 23460cctgagcctt tgcgccttca gagaagaaca tgccgcaaga cttgccggaa aactgattgg 23520ccggacaggc cgcgtcgtgc acgcagcacc ttgcgtcggt gttggagatc tgcaccacat 23580ttcggcccca ccggttcttc acgatcttgg ccttgctaga ctgctccttc agcgcgcgct 23640gcccgttttc gctcgtcaca tccatttcaa tcacgtgctc cttatttatc ataatgcttc 23700cgtgtagaca cttaagctcg ccttcgatct cagcgcagcg gtgcagccac aacgcgcagc 23760ccgtgggctc gtgatgcttg taggtcacct ctgcaaacga ctgcaggtac gcctgcagga 23820atcgccccat catcgtcaca aaggtcttgt tgctggtgaa ggtcagctgc aacccgcggt 23880gctcctcgtt cagccaggtc ttgcatacgg ccgccagagc ttccacttgg tcaggcagta 23940gtttgaagtt cgcctttaga tcgttatcca cgtggtactt gtccatcagc gcgcgcgcag 24000cctccatgcc cttctcccac gcagacacga tcggcacact cagcgggttc atcaccgtaa 24060tttcactttc cgcttcgctg ggctcttcct cttcctcttg cgtccgcata ccacgcgcca 24120ctgggtcgtc ttcattcagc cgccgcactg tgcgcttacc tcctttgcca tgcttgatta 24180gcaccggtgg gttgctgaaa cccaccattt gtagcgccac atcttctctt tcttcctcgc 24240tgtccacgat tacctctggt gatggcgggc gctcgggctt gggagaaggg cgcttctttt 24300tcttcttggg cgcaatggcc aaatccgccg ccgaggtcga tggccgcggg ctgggtgtgc 24360gcggcaccag cgcgtcttgt gatgagtctt cctcgtcctc ggactcgata cgccgcctca 24420tccgcttttt tgggggcgcc cggggaggcg gcggcgacgg ggacggggac gacacgtcct 24480ccatggttgg gggacgtcgc gccgcaccgc gtccgcgctc gggggtggtt tcgcgctgct 24540cctcttcccg actggccatt tccttctcct ataggcagaa aaagatcatg gagtcagtcg 24600agaagaagga cagcctaacc gccccctctg agttcgccac caccgcctcc accgatgccg 24660ccaacgcgcc taccaccttc cccgtcgagg cacccccgct tgaggaggag gaagtgatta 24720tcgagcagga cccaggtttt gtaagcgaag acgacgagga ccgctcagta ccaacagagg 24780ataaaaagca agaccaggac aacgcagagg caaacgagga acaagtcggg cggggggacg 24840aaaggcatgg cgactaccta gatgtgggag acgacgtgct gttgaagcat ctgcagcgcc 24900agtgcgccat tatctgcgac gcgttgcaag agcgcagcga tgtgcccctc gccatagcgg 24960atgtcagcct tgcctacgaa cgccacctat tctcaccgcg cgtacccccc aaacgccaag 25020aaaacggcac atgcgagccc aacccgcgcc tcaacttcta ccccgtattt gccgtgccag 25080aggtgcttgc cacctatcac atctttttcc aaaactgcaa gataccccta tcctgccgtg 25140ccaaccgcag ccgagcggac aagcagctgg ccttgcggca gggcgctgtc atacctgata 25200tcgcctcgct caacgaagtg ccaaaaatct ttgagggtct tggacgcgac gagaagcgcg 25260cggcaaacgc tctgcaacag gaaaacagcg aaaatgaaag tcactctgga gtgttggtgg 25320aactcgaggg tgacaacgcg cgcctagccg tactaaaacg cagcatcgag gtcacccact 25380ttgcctaccc ggcacttaac ctacccccca aggtcatgag cacagtcatg agtgagctga 25440tcgtgcgccg tgcgcagccc ctggagaggg atgcaaattt gcaagaacaa acagaggagg 25500gcctacccgc agttggcgac gagcagctag cgcgctggct tcaaacgcgc gagcctgccg 25560acttggagga gcgacgcaaa ctaatgatgg ccgcagtgct cgttaccgtg gagcttgagt 25620gcatgcagcg gttctttgct gacccggaga tgcagcgcaa gctagaggaa acattgcact 25680acacctttcg acagggctac gtacgccagg cctgcaagat ctccaacgtg gagctctgca 25740acctggtctc ctaccttgga attttgcacg aaaaccgcct tgggcaaaac gtgcttcatt 25800ccacgctcaa gggcgaggcg cgccgcgact acgtccgcga ctgcgtttac ttatttctat 25860gctacacctg gcagacggcc atgggcgttt ggcagcagtg cttggaggag tgcaacctca 25920aggagctgca gaaactgcta aagcaaaact tgaaggacct atggacggcc ttcaacgagc 25980gctccgtggc cgcgcacctg gcggacatca ttttccccga acgcctgctt aaaaccctgc 26040aacagggtct gccagacttc accagtcaaa gcatgttgca gaactttagg aactttatcc 26100tagagcgctc aggaatcttg cccgccacct gctgtgcact tcctagcgac tttgtgccca 26160ttaagtaccg cgaatgccct ccgccgcttt ggggccactg ctaccttctg cagctagcca 26220actaccttgc ctaccactct gacataatgg aagacgtgag cggtgacggt ctactggagt 26280gtcactgtcg ctgcaaccta tgcaccccgc accgctccct ggtttgcaat tcgcagctgc 26340ttaacgaaag tcaaattatc ggtacctttg agctgcaggg tccctcgcct gacgaaaagt 26400ccgcggctcc ggggttgaaa ctcactccgg ggctgtggac gtcggcttac cttcgcaaat 26460ttgtacctga ggactaccac gcccacgaga ttaggttcta cgaagaccaa tcccgcccgc 26520ctaatgcgga gcttaccgcc tgcgtcatta cccagggcca cattcttggc caattgcaag 26580ccatcaacaa agcccgccaa gagtttctgc tacgaaaggg acggggggtt tacttggacc 26640cccagtccgg cgaggagctc aacccaatcc ccccgccgcc gcagccctat cagcagcagc 26700cgcgggccct tgcttcccag gatggcaccc aaaaagaagc tgcagctgcc gccgccaccc 26760acggacgagg aggaatactg ggacagtcag gcagaggagg ttttggacga ggaggaggag 26820gacatgatgg aagactggga gagcctagac gaggaagctt ccgaggtcga agaggtgtca 26880gacgaaacac cgtcaccctc ggtcgcattc ccctcgccgg cgccccagaa atcggcaacc 26940ggttccagca tggctacaac ctccgctcct caggcgccgc cggcactgcc cgttcgccga 27000cccaaccgta gatgggacac cactggaacc agggccggta agtccaagca gccgccgccg 27060ttagcccaag agcaacaaca gcgccaaggc taccgctcat ggcgcgggca caagaacgcc 27120atagttgctt gcttgcaaga ctgtgggggc aacatctcct tcgcccgccg ctttcttctc 27180taccatcacg gcgtggcctt cccccgtaac atcctgcatt actaccgtca tctctacagc 27240ccatactgca ccggcggcag cggcagcaac agcagcggcc acacagaagc aaaggcgacc 27300ggatagcaag actctgacaa agcccaagaa atccacagcg gcggcagcag caggaggagg 27360agcgctgcgt ctggcgccca acgaacccgt atcgacccgc gagcttagaa acaggatttt 27420tcccactctg tatgctatat ttcaacagag caggggccaa gaacaagagc tgaaaataaa 27480aaacaggtct ctgcgatccc tcacccgcag ctgcctgtat cacaaaagcg aagatcagct 27540tcggcgcacg ctggaagacg cggaggctct cttcagtaaa tactgcgcgc tgactcttaa 27600ggactagttt cgcgcccttt ctcaaattta agcgcgaaaa ctacgtcatc tccagcggcc 27660acacccggcg ccagcacctg ttgtcagcgc cattatgagc aaggaaattc ccacgcccta 27720catgtggagt taccagccac aaatgggact tgcggctgga gctgcccaag actactcaac 27780ccgaataaac tacatgagcg cgggacccca catgatatcc cgggtcaacg gaatacgcgc 27840ccaccgaaac cgaattctcc tggaacaggc ggctattacc accacacctc gtaataacct 27900taatccccgt agttggcccg ctgccctggt gtaccaggaa agtcccgctc ccaccactgt 27960ggtacttccc agagacgccc aggccgaagt tcagatgact aactcagggg cgcagcttgc 28020gggcggcttt cgtcacaggg tgcggtcgcc cgggcagggt ataactcacc tgacaatcag 28080agggcgaggt attcagctca acgacgagtc ggtgagctcc tcgcttggtc tccgtccgga 28140cgggacattt cagatcggcg gcgccggccg ctcttcattc acgcctcgtc aggcaatcct 28200aactctgcag acctcgtcct ctgagccgcg ctctggaggc attggaactc tgcaatttat 28260tgaggagttt gtgccatcgg tctactttaa ccccttctcg ggacctcccg gccactatcc 28320ggatcaattt attcctaact ttgacgcggt aaaggactcg gcggacggct acgactgaat 28380gttaagtgga gaggcagagc aactgcgcct gaaacacctg gtccactgtc gccgccacaa 28440gtgctttgcc cgcgactccg gtgagttttg ctactttgaa ttgcccgagg atcatatcga 28500gggcccggcg cacggcgtcc ggcttaccgc ccagggagag cttgcccgta gcctgattcg 28560ggagtttacc cagcgccccc tgctagttga gcgggacagg ggaccctgtg ttctcactgt 28620gatttgcaac tgtcctaacc ctggattaca tcaagatctt tgttgccatc tctgtgctga 28680gtataataaa tacagaaatt aaaatatact ggggctccta tcgccatcct gtaaacgcca 28740ccgtcttcac ccgcccaagc aaaccaaggc gaaccttacc tggtactttt aacatctctc 28800cctctgtgat ttacaacagt ttcaacccag acggagtgag tctacgagag aacctctccg 28860agctcagcta ctccatcaga aaaaacacca ccctccttac ctgccgggaa cgtacgagtg 28920cgtcaccggc cgctgcacca cacctaccgc ctgaccgtaa accagacttt ttccggacag 28980acctcaataa ctctgtttac cagaacagga ggtgagctta gaaaaccctt agggtattag 29040gccaaaggcg cagctactgt ggggtttatg aacaattcaa gcaactctac gggctattct 29100aattcaggtt tctctagaat cggggttggg gttattctct gtcttgtgat tctctttatt 29160cttatactaa cgcttctctg cctaaggctc gccgcctgct gtgtgcacat ttgcatttat 29220tgtcagcttt ttaaacgctg gggtcgccac ccaagatgat taggtacata atcctaggtt 29280tactcaccct tgcgtcagcc cacggtacca cccaaaaggt ggattttaag gagccagcct 29340gtaatgttac attcgcagct gaagctaatg agtgcaccac tcttataaaa tgcaccacag 29400aacatgaaaa gctgcttatt cgccacaaaa acaaaattgg caagtatgct gtttatgcta 29460tttggcagcc aggtgacact acagagtata atgttacagt tttccagggt aaaagtcata 29520aaacttttat gtatactttt ccattttatg aaatgtgcga cattaccatg tacatgagca 29580aacagtataa gttgtggccc ccacaaaatt gtgtggaaaa cactggcact ttctgctgca 29640ctgctatgct aattacagtg ctcgctttgg tctgtaccct actctatatt aaatacaaaa 29700gcagacgcag ctttattgag gaaaagaaaa tgccttaatt tactaagtta caaagctaat 29760gtcaccacta actgctttac tcgctgcttg caaaacaaat tcaaaaagtt agcattataa 29820ttagaatagg atttaaaccc cccggtcatt tcctgctcaa taccattccc ctgaacaatt 29880gactctatgt gggatatgct ccagcgctac aaccttgaag tcaggcttcc tggatgtcag 29940catctgactt tggccagcac ctgtcccgcg gatttgttcc agtccaacta cagcgaccca 30000ccctaacaga gatgaccaac acaaccaacg cggccgccgc taccggactt acatctacca 30060caaatacacc ccaagtttct gcctttgtca ataactggga taacttgggc atgtggtggt 30120tctccatagc gcttatgttt gtatgcctta ttattatgtg gctcatctgc tgcctaaagc 30180gcaaacgcgc ccgaccaccc atctatagtc ccatcattgt gctacaccca aacaatgatg 30240gaatccatag attggacgga ctgaaacaca tgttcttttc tcttacagta tgattaaatg 30300agacatgatt cctcgagttt ttatattact gacccttgtt gcgctttttt tgtgcgtgct 30360ccacattggc tgcggtttct cacatcgaag tagactgcat tccagccttc acagtctatt 30420tgctttacgg atttgtcacc ctcacgctca tctgcagcct catcactgtg gtcatcgcct 30480ttatccagtg cattgactgg gtctgtgtgc gctttgcata tctcagacac catccccagt 30540acagggacag gactatagct gagcttctta gaattcttta attatgaaat ttactgtgac 30600ttttctgctg attatttgca ccctatctgc gttttgttcc ccgacctcca agcctcaaag 30660acatatatca tgcagattca ctcgtatatg gaatattcca agttgctaca atgaaaaaag 30720cgatctttcc gaagcctggt tatatgcaat catctctgtt atggtgttct gcagtaccat 30780cttagcccta gctatatatc cctaccttga cattggctgg aacgcaatag atgccatgaa 30840ccacccaact ttccccgcgc ccgctatgct tccactgcaa caagttgttg ccggcggctt 30900tgtcccagcc aatcagcctc gcccaccttc tcccaccccc actgaaatca gctactttaa 30960tctaacagga ggagatgact gacaccctag atctagaaat ggacggaatt attacagagc 31020agcgcctgct agaaagacgc agggcagcgg ccgagcaaca gcgcatgaat caagagctcc 31080aagacatggt taacttgcac cagtgcaaaa ggggtatctt ttgtctggta aagcaggcca 31140aagtcaccta cgacagtaat accaccggac accgccttag ctacaagttg ccaaccaagc 31200gtcagaaatt ggtggtcatg gtgggagaaa agcccattac cataactcag cactcggtag 31260aaaccgaagg ctgcattcac tcaccttgtc aaggacctga ggatctctgc acccttatta 31320agaccctgtg cggtctcaaa gatcttattc cctttaacta ataaaaaaaa ataataaagc 31380atcacttact taaaatcagt tagcaaattt ctgtccagtt tattcagcag cacctccttg 31440ccctcctccc agctctggta ttgcagcttc ctcctggctg caaactttct ccacaatcta 31500aatggaatgt cagtttcctc ctgttcctgt ccatccgcac ccactatctt catgttgttg 31560cagatgaagc gcgcaagacc gtctgaagat accttcaacc ccgtgtatcc atatgacacg 31620gaaaccggtc ctccaactgt gccttttctt actcctccct ttgtatcccc caatgggttt 31680caagagagtc cccctggggt actctctttg cgcctatccg aacctctagt tacctccaat 31740ggcatgcttg cgctcaaaat gggcaacggc ctctctctgg acgaggccgg caaccttacc 31800tcccaaaatg taaccactgt gagcccacct ctcaaaaaaa ccaagtcaaa cataaacctg 31860gaaatatctg cacccctcac agttacctca gaagccctaa ctgtggctgc cgccgcacct 31920ctaatggtcg cgggcaacac actcaccatg caatcacagg ccccgctaac cgtgcacgac 31980tccaaactta gcattgccac ccaaggaccc ctcacagtgt cagaaggaaa gctagccctg 32040caaacatcag gccccctcac caccaccgat agcagtaccc ttactatcac tgcctcaccc 32100cctctaacta ctgccactgg tagcttgggc attgacttga aagagcccat ttatacacaa 32160aatggaaaac taggactaaa gtacggggct cctttgcatg taacagacga cctaaacact 32220ttgaccgtag caactggtcc aggtgtgact attaataata cttccttgca aactaaagtt 32280actggagcct tgggttttga ttcacaaggc aatatgcaac ttaatgtagc aggaggacta 32340aggattgatt ctcaaaacag acgccttata cttgatgtta gttatccgtt tgatgctcaa 32400aaccaactaa atctaagact aggacagggc cctcttttta taaactcagc ccacaacttg 32460gatattaact acaacaaagg cctttacttg tttacagctt caaacaattc caaaaagctt 32520gaggttaacc taagcactgc caaggggttg atgtttgacg ctacagccat agccattaat 32580gcaggagatg ggcttgaatt tggttcacct aatgcaccaa acacaaatcc cctcaaaaca 32640aaaattggcc atggcctaga atttgattca aacaaggcta tggttcctaa actaggaact 32700ggccttagtt ttgacagcac aggtgccatt acagtaggaa acaaaaataa tgataagcta 32760actttgtgga ccacaccagc tccatctcct aactgtagac taaatgcaga gaaagatgct 32820aaactcactt tggtcttaac aaaatgtggc agtcaaatac ttgctacagt ttcagttttg 32880gctgttaaag gcagtttggc tccaatatct ggaacagttc aaagtgctca tcttattata 32940agatttgacg aaaatggagt gctactaaac aattccttcc tggacccaga atattggaac 33000tttagaaatg gagatcttac tgaaggcaca gcctatacaa acgctgttgg atttatgcct 33060aacctatcag cttatccaaa atctcacggt aaaactgcca aaagtaacat tgtcagtcaa 33120gtttacttaa acggagacaa aactaaacct gtaacactaa ccattacact aaacggtaca 33180caggaaacag gagacacaac tccaagtgca tactctatgt cattttcatg ggactggtct 33240ggccacaact acattaatga aatatttgcc acatcctctt acactttttc atacattgcc 33300caagaataaa gaatcgtttg tgttatgttt caacgtgttt atttttcaat tgcagaaaat 33360ttcaagtcat ttttcattca gtagtatagc cccaccacca catagcttat acagatcacc 33420gtaccttaat caaactcaca gaaccctagt attcaacctg ccacctccct cccaacacac 33480agagtacaca gtcctttctc cccggctggc cttaaaaagc atcatatcat gggtaacaga 33540catattctta ggtgttatat tccacacggt ttcctgtcga gccaaacgct catcagtgat 33600attaataaac tccccgggca gctcacttaa gttcatgtcg ctgtccagct gctgagccac 33660aggctgctgt ccaacttgcg gttgcttaac gggcggcgaa ggagaagtcc acgcctacat 33720gggggtagag tcataatcgt gcatcaggat agggcggtgg tgctgcagca gcgcgcgaat 33780aaactgctgc cgccgccgct ccgtcctgca ggaatacaac atggcagtgg tctcctcagc 33840gatgattcgc accgcccgca gcataaggcg ccttgtcctc cgggcacagc agcgcaccct 33900gatctcactt aaatcagcac agtaactgca gcacagcacc acaatattgt tcaaaatccc 33960acagtgcaag gcgctgtatc caaagctcat ggcggggacc acagaaccca cgtggccatc 34020ataccacaag cgcaggtaga ttaagtggcg acccctcata aacacgctgg acataaacat 34080tacctctttt ggcatgttgt aattcaccac ctcccggtac catataaacc tctgattaaa 34140catggcgcca tccaccacca tcctaaacca gctggccaaa acctgcccgc cggctataca 34200ctgcagggaa ccgggactgg aacaatgaca gtggagagcc caggactcgt aaccatggat 34260catcatgctc gtcatgatat caatgttggc acaacacagg cacacgtgca tacacttcct 34320caggattaca agctcctccc gcgttagaac catatcccag ggaacaaccc attcctgaat 34380cagcgtaaat cccacactgc agggaagacc tcgcacgtaa ctcacgttgt gcattgtcaa 34440agtgttacat tcgggcagca gcggatgatc ctccagtatg gtagcgcggg tttctgtctc 34500aaaaggaggt agacgatccc tactgtacgg agtgcgccga gacaaccgag atcgtgttgg 34560tcgtagtgtc atgccaaatg gaacgccgga cgtagtcata tttcctgaag caaaaccagg 34620tgcgggcgtg acaaacagat ctgcgtctcc ggtctcgccg cttagatcgc tctgtgtagt 34680agttgtagta tatccactct ctcaaagcat ccaggcgccc cctggcttcg ggttctatgt 34740aaactccttc atgcgccgct gccctgataa catccaccac cgcagaataa gccacaccca 34800gccaacctac acattcgttc tgcgagtcac acacgggagg agcgggaaga gctggaagaa 34860ccatgttttt ttttttattc caaaagatta tccaaaacct caaaatgaag atctattaag 34920tgaacgcgct cccctccggt ggcgtggtca aactctacag ccaaagaaca gataatggca 34980tttgtaagat gttgcacaat ggcttccaaa aggcaaacgg ccctcacgtc caagtggacg 35040taaaggctaa acccttcagg gtgaatctcc tctataaaca ttccagcacc ttcaaccatg 35100cccaaataat tctcatctcg ccaccttctc aatatatctc taagcaaatc ccgaatatta 35160agtccggcca ttgtaaaaat ctgctccaga gcgccctcca ccttcagcct caagcagcga 35220atcatgattg caaaaattca ggttcctcac agacctgtat aagattcaaa agcggaacat 35280taacaaaaat accgcgatcc cgtaggtccc ttcgcagggc cagctgaaca taatcgtgca 35340ggtctgcacg gaccagcgcg gccacttccc cgccaggaac catgacaaaa gaacccacac 35400tgattatgac acgcatactc ggagctatgc taaccagcgt agccccgatg taagcttgtt 35460gcatgggcgg cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaa gcctcgcgca 35520aaaaagaaag cacatcgtag tcatgctcat gcagataaag gcaggtaagc tccggaacca 35580ccacagaaaa agacaccatt tttctctcaa acatgtctgc gggtttctgc ataaacacaa 35640aataaaataa caaaaaaaca tttaaacatt agaagcctgt cttacaacag gaaaaacaac 35700ccttataagc ataagacgga ctacggccat gccggcgtga ccgtaaaaaa actggtcacc 35760gtgattaaaa agcaccaccg acagctcctc ggtcatgtcc ggagtcataa tgtaagactc 35820ggtaaacaca tcaggttgat tcacatcggt cagtgctaaa aagcgaccga aatagcccgg 35880gggaatacat acccgcaggc gtagagacaa cattacagcc cccataggag gtataacaaa 35940attaatagga gagaaaaaca cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc 36000accctcccgc tccagaacaa catacagcgc ttccacagcg gcagccataa cagtcagcct 36060taccagtaaa aaagaaaacc tattaaaaaa acaccactcg acacggcacc agctcaatca 36120gtcacagtgt aaaaaagggc caagtgcaga gcgagtatat ataggactaa aaaatgacgt 36180aacggttaaa gtccacaaaa aacacccaga aaaccgcacg cgaacctacg cccagaaacg 36240aaagccaaaa aacccacaac ttcctcaaat cgtcacttcc gttttcccac gttacgtcac 36300ttcccatttt aagaaaacta caattcccaa cacatacaag ttactccgcc ctaaaaccta 36360cgtcacccgc cccgttccca cgccccgcgc cacgtcacaa actccacccc ctcattatca 36420tattggcttc aatccaaaat aaggtatatt attgatgatg 364601035203DNAArtificial sequencePPE-1-3X-FasC virl construct (lacking repeats) 10catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420cgggtcaaag ttggcgtttt attattatag tcagtacgta cgtgtacttc tgatcggcga 480tactagggag ataaggatgt acctgacaaa accacattgt tgttgttatc attattattt 540agttttcctt ccttgctaac tcctgacgga atctttctca cctcaaatgc gaagtacttt 600agtttagaaa agacttggtg gaaggggtgg tggtggaaaa gtagggtgat cttccaaact 660aatctggttc cccgcccgcc ccagtagctg ggattcaaga gcgaagagtg gggatcgtcc 720ccttgtttga tcagaaagac ataaaaggaa aatcaagtga acaatgatca gccccacctc 780caccccaccc ccctgcgcgc gcacaataca atctatttaa ttgtacttca tacttttcat 840tccaatgggg tgactttgct tctggagaaa ctcttgattc ttgaactctg gggctggcag 900ctagcctcca gaagcaaagt caccccattg gaatgaaaag tatgaagtac aatgaaaagt 960atgaagtact ggctccagaa gcaaagtcac cctccagaag caaagtcacc ccattggaat 1020gaaaagtatg aagtacgcta gcaaaagggg aagcgggctg ctgctctctg caggttctgc 1080agcggtctct gtctagtggg tgttttcttt ttcttagccc tgcccctgga ttgtcagacg 1140gcgggcgtct

gcctctgaag ttagccgtga tttcctctag agccgggtct tatctctggc 1200tgcacgttgc ctgtgggtga ctaatcacac aataacattg tttagggctg gaataaagtc 1260agagctgttt acccccactc tataggggtt caatataaaa aggcggcgga gaactgtccg 1320agtcagaagc gttcctgcac cggcgctgag agcctgaccc ggtctgctcc gctgtccttg 1380cgcgctgcct cccggctgcc cgcgacgctt tcgccccagt ggaagggcca cttgctgcgg 1440ccgctaattc tgcagatcgg gatccggcat gggcctctcc accgtgcctg acctgctgct 1500gccgctggtg ctcctggagc tgttggtggg aatatacccc tcaggggtta ttggactggt 1560ccctcaccta ggggacaggg agaagagaga tagtgtgtgt ccccaaggaa aatatatcca 1620ccctcaaaat aattcgattt gctgtaccaa gtgccacaaa ggaacctact tgtacaatga 1680ctgtccaggc ccggggcagg atacggactg cagggagtgt gagagcggct ccttcaccgc 1740ttcagaaaac cacctcagac actgcctcag ctgctccaaa tgccgaaagg aaatgggtca 1800ggtggagatc tcttcttgca cagtggaccg ggacaccgtg tgtggctgca ggaagaacca 1860gtaccggcat tattggagtg aaaacctttt ccagtgcttc aattgcagcc tctgcctcaa 1920tgggaccgtg cacctctcct gccaggagaa acagaacacc gtgtgcacct gccatgcagg 1980tttctttcta agagaaaacg agtgtgtctc ctgtagtaac tgtaagaaaa gcctggagtg 2040cacgaagttg tgcctaccaa gcttaggatc cagatctaac ttggggtggc tttgtcttct 2100tcttttgcca attccactaa ttgtttgggt gaagagaaag gaagtacaga aaacatgcag 2160aaagcacaga aaggaaaacc aaggttctca tgaatctcca accttaaatc ctgaaacagt 2220ggcaataaat ttatctgatg ttgacttgag taaatatatc accactattg ctggagtcat 2280gacactaagt caagttaaag gctttgttcg aaagaatggt gtcaatgaag ccaaaataga 2340tgagatcaag aatgacaatg tccaagacac agcagaacag aaagttcaac tgcttcgtaa 2400ttggcatcaa cttcatggaa agaaagaagc gtatgacaca ttgattaaag atctcaaaaa 2460agccaatctt tgtactcttg cagagaaaat tcagactatc atcctcaagg acattactag 2520tgactcagaa aattcaaact tcagaaatga aatccaaagc ttggtctagc tcgagcatgc 2580atctaggcgg ccgcatggca gaaattcgcg aattcgctag cgttaacgga tcctctagac 2640gagatccgaa cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa 2700atttcacaaa taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca 2760atgtatctta tcatgtctag atctgtactg aaatgtgtgg gcgtggctta agggtgggaa 2820agaatatata aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg 2880ccatgagcac caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc 2940ccccatgggc cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc 3000tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg 3060cagcctccgc cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg 3120ctttcctgag cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt 3180tgacggctct tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc 3240agctgttgga tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg 3300tttaaaacat aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct 3360gtctttattt aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga 3420gggtcctgtg tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg 3480gcataagccc gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg 3540tgttgtagat gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca 3600gtagcaagct gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct 3660gggatgggtg catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta 3720tgttcccagc catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc 3780cggtgcactt gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga 3840cgcccttgtg acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac 3900gggcggcggc ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga 3960tgagatcgtc ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa 4020tggttccatc cggcccaggg gcgtagttac cctcacagat ttgcatttcc cacgctttga 4080gttcagatgg ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag 4140gggagatcag ctgggaagaa agcaggttcc tgagcagctg cgacttaccg cagccggtgg 4200gcccgtaaat cacacctatt accggctgca actggtagtt aagagagctg cagctgccgt 4260catccctgag caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga 4320ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt 4380ttttcaacgg tttgagaccg tccgccgtag gcatgctttt gagcgtttga ccaagcagtt 4440ccaggcggtc ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc 4500gtttcgcggg ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc 4560cagggtcatg tctttccacg ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa 4620ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg aggctggtcc tgctggtgct 4680gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata 4740gtccagcccc tccgcggcgt ggcccttggc gcgcagcttg cccttggagg aggcgccgca 4800cgaggggcag tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg 4860ggagtaggca tccgcgccgc aggccccgca gacggtctcg cattccacga gccaggtgag 4920ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc 4980tctggtttcc atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta 5040tacagacttg agaggcctgt cctcgagcgg tgttccgcgg tcctcctcgt atagaaactc 5100ggaccactct gagacaaagg ctcgcgtcca ggccagcacg aaggaggcta agtgggaggg 5160gtagcggtcg ttgtccacta gggggtccac tcgctccagg gtgtgaagac acatgtcgcc 5220ctcttcggca tcaaggaagg tgattggttt gtaggtgtag gccacgtgac cgggtgttcc 5280tgaagggggg ctataaaagg gggtgggggc gcgttcgtcc tcactctctt ccgcatcgct 5340gtctgcgagg gccagctgtt ggggtgagta ctccctctga aaagcgggca tgacttctgc 5400gctaagattg tcagtttcca aaaacgagga ggatttgata ttcacctggc ccgcggtgat 5460gcctttgagg gtggccgcat ccatctggtc agaaaagaca atctttttgt tgtcaagctt 5520ggtggcaaac gacccgtaga gggcgttgga cagcaacttg gcgatggagc gcagggtttg 5580gtttttgtcg cgatcggcgc gctccttggc cgcgatgttt agctgcacgt attcgcgcgc 5640aacgcaccgc cattcgggaa agacggtggt gcgctcgtcg ggcaccaggt gcacgcgcca 5700accgcggttg tgcagggtga caaggtcaac gctggtggct acctctccgc gtaggcgctc 5760gttggtccag cagaggcggc cgcccttgcg cgagcagaat ggcggtaggg ggtctagctg 5820cgtctcgtcc ggggggtctg cgtccacggt aaagaccccg ggcagcaggc gcgcgtcgaa 5880gtagtctatc ttgcatcctt gcaagtctag cgcctgctgc catgcgcggg cggcaagcgc 5940gcgctcgtat gggttgagtg ggggacccca tggcatgggg tgggtgagcg cggaggcgta 6000catgccgcaa atgtcgtaaa cgtagagggg ctctctgagt attccaagat atgtagggta 6060gcatcttcca ccgcggatgc tggcgcgcac gtaatcgtat agttcgtgcg agggagcgag 6120gaggtcggga ccgaggttgc tacgggcggg ctgctctgct cggaagacta tctgcctgaa 6180gatggcatgt gagttggatg atatggttgg acgctggaag acgttgaagc tggcgtctgt 6240gagacctacc gcgtcacgca cgaaggaggc gtaggagtcg cgcagcttgt tgaccagctc 6300ggcggtgacc tgcacgtcta gggcgcagta gtccagggtt tccttgatga tgtcatactt 6360atcctgtccc ttttttttcc acagctcgcg gttgaggaca aactcttcgc ggtctttcca 6420gtactcttgg atcggaaacc cgtcggcctc cgaacggtaa gagcctagca tgtagaactg 6480gttgacggcc tggtaggcgc agcatccctt ttctacgggt agcgcgtatg cctgcgcggc 6540cttccggagc gaggtgtggg tgagcgcaaa ggtgtccctg accatgactt tgaggtactg 6600gtatttgaag tcagtgtcgt cgcatccgcc ctgctcccag agcaaaaagt ccgtgcgctt 6660tttggaacgc ggatttggca gggcgaaggt gacatcgttg aagagtatct ttcccgcgcg 6720aggcataaag ttgcgtgtga tgcggaaggg tcccggcacc tcggaacggt tgttaattac 6780ctgggcggcg agcacgatct cgtcaaagcc gttgatgttg tggcccacaa tgtaaagttc 6840caagaagcgc gggatgccct tgatggaagg caatttttta agttcctcgt aggtgagctc 6900ttcaggggag ctgagcccgt gctctgaaag ggcccagtct gcaagatgag ggttggaagc 6960gacgaatgag ctccacaggt cacgggccat tagcatttgc aggtggtcgc gaaaggtcct 7020aaactggcga cctatggcca ttttttctgg ggtgatgcag tagaaggtaa gcgggtcttg 7080ttcccagcgg tcccatccaa ggttcgcggc taggtctcgc gcggcagtca ctagaggctc 7140atctccgccg aacttcatga ccagcatgaa gggcacgagc tgcttcccaa aggcccccat 7200ccaagtatag gtctctacat cgtaggtgac aaagagacgc tcggtgcgag gatgcgagcc 7260gatcgggaag aactggatct cccgccacca attggaggag tggctattga tgtggtgaaa 7320gtagaagtcc ctgcgacggg ccgaacactc gtgctggctt ttgtaaaaac gtgcgcagta 7380ctggcagcgg tgcacgggct gtacatcctg cacgaggttg acctgacgac cgcgcacaag 7440gaagcagagt gggaatttga gcccctcgcc tggcgggttt ggctggtggt cttctacttc 7500ggctgcttgt ccttgaccgt ctggctgctc gaggggagtt acggtggatc ggaccaccac 7560gccgcgcgag cccaaagtcc agatgtccgc gcgcggcggt cggagcttga tgacaacatc 7620gcgcagatgg gagctgtcca tggtctggag ctcccgcggc gtcaggtcag gcgggagctc 7680ctgcaggttt acctcgcata gacgggtcag ggcgcgggct agatccaggt gatacctaat 7740ttccaggggc tggttggtgg cggcgtcgat ggcttgcaag aggccgcatc cccgcggcgc 7800gactacggta ccgcgcggcg ggcggtgggc cgcgggggtg tccttggatg atgcatctaa 7860aagcggtgac gcgggcgagc ccccggaggt agggggggct ccggacccgc cgggagaggg 7920ggcaggggca cgtcggcgcc gcgcgcgggc aggagctggt gctgcgcgcg taggttgctg 7980gcgaacgcga cgacgcggcg gttgatctcc tgaatctggc gcctctgcgt gaagacgacg 8040ggcccggtga gcttgaacct gaaagagagt tcgacagaat caatttcggt gtcgttgacg 8100gcggcctggc gcaaaatctc ctgcacgtct cctgagttgt cttgataggc gatctcggcc 8160atgaactgct cgatctcttc ctcctggaga tctccgcgtc cggctcgctc cacggtggcg 8220gcgaggtcgt tggaaatgcg ggccatgagc tgcgagaagg cgttgaggcc tccctcgttc 8280cagacgcggc tgtagaccac gcccccttcg gcatcgcggg cgcgcatgac cacctgcgcg 8340agattgagct ccacgtgccg ggcgaagacg gcgtagtttc gcaggcgctg aaagaggtag 8400ttgagggtgg tggcggtgtg ttctgccacg aagaagtaca taacccagcg tcgcaacgtg 8460gattcgttga tatcccccaa ggcctcaagg cgctccatgg cctcgtagaa gtccacggcg 8520aagttgaaaa actgggagtt gcgcgccgac acggttaact cctcctccag aagacggatg 8580agctcggcga cagtgtcgcg cacctcgcgc tcaaaggcta caggggcctc ttcttcttct 8640tcaatctcct cttccataag ggcctcccct tcttcttctt ctggcggcgg tgggggaggg 8700gggacacggc ggcgacgacg gcgcaccggg aggcggtcga caaagcgctc gatcatctcc 8760ccgcggcgac ggcgcatggt ctcggtgacg gcgcggccgt tctcgcgggg gcgcagttgg 8820aagacgccgc ccgtcatgtc ccggttatgg gttggcgggg ggctgccatg cggcagggat 8880acggcgctaa cgatgcatct caacaattgt tgtgtaggta ctccgccgcc gagggacctg 8940agcgagtccg catcgaccgg atcggaaaac ctctcgagaa aggcgtctaa ccagtcacag 9000tcgcaaggta ggctgagcac cgtggcgggc ggcagcgggc ggcggtcggg gttgtttctg 9060gcggaggtgc tgctgatgat gtaattaaag taggcggtct tgagacggcg gatggtcgac 9120agaagcacca tgtccttggg tccggcctgc tgaatgcgca ggcggtcggc catgccccag 9180gcttcgtttt gacatcggcg caggtctttg tagtagtctt gcatgagcct ttctaccggc 9240acttcttctt ctccttcctc ttgtcctgca tctcttgcat ctatcgctgc ggcggcggcg 9300gagtttggcc gtaggtggcg ccctcttcct cccatgcgtg tgaccccgaa gcccctcatc 9360ggctgaagca gggctaggtc ggcgacaacg cgctcggcta atatggcctg ctgcacctgc 9420gtgagggtag actggaagtc atccatgtcc acaaagcggt ggtatgcgcc cgtgttgatg 9480gtgtaagtgc agttggccat aacggaccag ttaacggtct ggtgacccgg ctgcgagagc 9540tcggtgtacc tgagacgcga gtaagccctc gagtcaaata cgtagtcgtt gcaagtccgc 9600accaggtact ggtatcccac caaaaagtgc ggcggcggct ggcggtagag gggccagcgt 9660agggtggccg gggctccggg ggcgagatct tccaacataa ggcgatgata tccgtagatg 9720tacctggaca tccaggtgat gccggcggcg gtggtggagg cgcgcggaaa gtcgcggacg 9780cggttccaga tgttgcgcag cggcaaaaag tgctccatgg tcgggacgct ctggccggtc 9840aggcgcgcgc aatcgttgac gctctagacc gtgcaaaagg agagcctgta agcgggcact 9900cttccgtggt ctggtggata aattcgcaag ggtatcatgg cggacgaccg gggttcgagc 9960cccgtatccg gccgtccgcc gtgatccatg cggttaccgc ccgcgtgtcg aacccaggtg 10020tgcgacgtca gacaacgggg gagtgctcct tttggcttcc ttccaggcgc ggcggctgct 10080gcgctagctt ttttggccac tggccgcgcg cagcgtaagc ggttaggctg gaaagcgaaa 10140gcattaagtg gctcgctccc tgtagccgga gggttatttt ccaagggttg agtcgcggga 10200cccccggttc gagtctcgga ccggccggac tgcggcgaac gggggtttgc ctccccgtca 10260tgcaagaccc cgcttgcaaa ttcctccgga aacagggacg agcccctttt ttgcttttcc 10320cagatgcatc cggtgctgcg gcagatgcgc ccccctcctc agcagcggca agagcaagag 10380cagcggcaga catgcagggc accctcccct cctcctaccg cgtcaggagg ggcgacatcc 10440gcggttgacg cggcagcaga tggtgattac gaacccccgc ggcgccgggc ccggcactac 10500ctggacttgg aggagggcga gggcctggcg cggctaggag cgccctctcc tgagcggcac 10560ccaagggtgc agctgaagcg tgatacgcgt gaggcgtacg tgccgcggca gaacctgttt 10620cgcgaccgcg agggagagga gcccgaggag atgcgggatc gaaagttcca cgcagggcgc 10680gagctgcggc atggcctgaa tcgcgagcgg ttgctgcgcg aggaggactt tgagcccgac 10740gcgcgaaccg ggattagtcc cgcgcgcgca cacgtggcgg ccgccgacct ggtaaccgca 10800tacgagcaga cggtgaacca ggagattaac tttcaaaaaa gctttaacaa ccacgtgcgt 10860acgcttgtgg cgcgcgagga ggtggctata ggactgatgc atctgtggga ctttgtaagc 10920gcgctggagc aaaacccaaa tagcaagccg ctcatggcgc agctgttcct tatagtgcag 10980cacagcaggg acaacgaggc attcagggat gcgctgctaa acatagtaga gcccgagggc 11040cgctggctgc tcgatttgat aaacatcctg cagagcatag tggtgcagga gcgcagcttg 11100agcctggctg acaaggtggc cgccatcaac tattccatgc ttagcctggg caagttttac 11160gcccgcaaga tataccatac cccttacgtt cccatagaca aggaggtaaa gatcgagggg 11220ttctacatgc gcatggcgct gaaggtgctt accttgagcg acgacctggg cgtttatcgc 11280aacgagcgca tccacaaggc cgtgagcgtg agccggcggc gcgagctcag cgaccgcgag 11340ctgatgcaca gcctgcaaag ggccctggct ggcacgggca gcggcgatag agaggccgag 11400tcctactttg acgcgggcgc tgacctgcgc tgggccccaa gccgacgcgc cctggaggca 11460gctggggccg gacctgggct ggcggtggca cccgcgcgcg ctggcaacgt cggcggcgtg 11520gaggaatatg acgaggacga tgagtacgag ccagaggacg gcgagtacta agcggtgatg 11580tttctgatca gatgatgcaa gacgcaacgg acccggcggt gcgggcggcg ctgcagagcc 11640agccgtccgg ccttaactcc acggacgact ggcgccaggt catggaccgc atcatgtcgc 11700tgactgcgcg caatcctgac gcgttccggc agcagccgca ggccaaccgg ctctccgcaa 11760ttctggaagc ggtggtcccg gcgcgcgcaa accccacgca cgagaaggtg ctggcgatcg 11820taaacgcgct ggccgaaaac agggccatcc ggcccgacga ggccggcctg gtctacgacg 11880cgctgcttca gcgcgtggct cgttacaaca gcggcaacgt gcagaccaac ctggaccggc 11940tggtggggga tgtgcgcgag gccgtggcgc agcgtgagcg cgcgcagcag cagggcaacc 12000tgggctccat ggttgcacta aacgccttcc tgagtacaca gcccgccaac gtgccgcggg 12060gacaggagga ctacaccaac tttgtgagcg cactgcggct aatggtgact gagacaccgc 12120aaagtgaggt gtaccagtct gggccagact attttttcca gaccagtaga caaggcctgc 12180agaccgtaaa cctgagccag gctttcaaaa acttgcaggg gctgtggggg gtgcgggctc 12240ccacaggcga ccgcgcgacc gtgtctagct tgctgacgcc caactcgcgc ctgttgctgc 12300tgctaatagc gcccttcacg gacagtggca gcgtgtcccg ggacacatac ctaggtcact 12360tgctgacact gtaccgcgag gccataggtc aggcgcatgt ggacgagcat actttccagg 12420agattacaag tgtcagccgc gcgctggggc aggaggacac gggcagcctg gaggcaaccc 12480taaactacct gctgaccaac cggcggcaga agatcccctc gttgcacagt ttaaacagcg 12540aggaggagcg cattttgcgc tacgtgcagc agagcgtgag ccttaacctg atgcgcgacg 12600gggtaacgcc cagcgtggcg ctggacatga ccgcgcgcaa catggaaccg ggcatgtatg 12660cctcaaaccg gccgtttatc aaccgcctaa tggactactt gcatcgcgcg gccgccgtga 12720accccgagta tttcaccaat gccatcttga acccgcactg gctaccgccc cctggtttct 12780acaccggggg attcgaggtg cccgagggta acgatggatt cctctgggac gacatagacg 12840acagcgtgtt ttccccgcaa ccgcagaccc tgctagagtt gcaacagcgc gagcaggcag 12900aggcggcgct gcgaaaggaa agcttccgca ggccaagcag cttgtccgat ctaggcgctg 12960cggccccgcg gtcagatgct agtagcccat ttccaagctt gatagggtct cttaccagca 13020ctcgcaccac ccgcccgcgc ctgctgggcg aggaggagta cctaaacaac tcgctgctgc 13080agccgcagcg cgaaaaaaac ctgcctccgg catttcccaa caacgggata gagagcctag 13140tggacaagat gagtagatgg aagacgtacg cgcaggagca cagggacgtg ccaggcccgc 13200gcccgcccac ccgtcgtcaa aggcacgacc gtcagcgggg tctggtgtgg gaggacgatg 13260actcggcaga cgacagcagc gtcctggatt tgggagggag tggcaacccg tttgcgcacc 13320ttcgccccag gctggggaga atgttttaaa aaaaaaaaaa gcatgatgca aaataaaaaa 13380ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt atgcggcgcg 13440cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc gcggcgccag 13500tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt gtgcctccgc 13560ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg gcacccctat 13620tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca tccctgaact 13680accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac tacagcccgg 13740gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc ggcgacctga 13800aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc aataagttta 13860aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag ctgaaatacg 13920agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc atagacctta 13980tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg gttctggaaa 14040gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac cccgtcactg 14100gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc attttgctgc 14160caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc atccgcaagc 14220ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt ggtaacattc 14280ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc gaacagggcg 14340ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac tccaacgcgg 14400cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc ggcgacacct 14460ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa gctgccgccc 14520ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa cccctgacag 14580aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc acccagtacc 14640gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc tcatggaccc 14700tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg ttgccagaca 14760tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt ccggtggtgg 14820gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc gtctactccc 14880aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc gagaaccaga 14940ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt cctgctctca 15000cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga gtgaccatta 15060ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata gtctcgccgc 15120gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg cccagcaata 15180acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag aagcgctccg 15240accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg cacaaacgcg 15300gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag gaggcgcgca 15360actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag accgtggtgc 15420gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca cgtcgccacc 15480gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac cgcgcacgtc 15540gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt attgtcactg 15600tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt agtgctatga 15660ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc ctgcgcgtgc 15720ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta gactcgtact 15780gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc aaaatcaaag 15840aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag gaagagcagg 15900attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat gatgatgaac 15960ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta cagtggaaag 16020gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg cccggtgagc 16080gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag gacctgcttg 16140agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag gacatgctgg 16200cgttgccgct

ggacgagggc aacccaacac ctagcctaaa gcccgtaaca ctgcagcagg 16260tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag tctggtgact 16320tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat gtcttggaaa 16380aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc aagcaggtgg 16440cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt agcaccagta 16500ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca gcggtggcgg 16560atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag gtgcaaacgg 16620acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg ccgttcgagg aagtacggcg 16680ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct acccccggct 16740atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga accaccactg 16800gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc gtgcgcaggg 16860tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac cccagcatcg 16920tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc ctccgtttcc 16980cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc cacggcctga 17040cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt cgcatgcgcg 17100gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc gtgcccggaa 17160ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc atgtggaaaa 17220atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt ttgtagaatg 17280gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt catgggaaac 17340tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg ctcgctgtgg 17400agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc ctggaacagc 17460agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca aaaggtggta 17520gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc agtgcaaaat 17580aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc ggccgtggag 17640acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga agaaactctg 17700gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg cctgcccacc 17760acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc cgtaacgctg 17820gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc gaccgccgtt 17880gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc gcgatcgttg 17940cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg tctgggggtg 18000caatccctga agcgccgacg atgcttctga tagctaacgt gtcgtatgtg tgtcatgtat 18060gcgtccatgt cgccgccaga ggagctgctg agccgccgcg cgcccgcttt ccaagatggc 18120taccccttcg atgatgccgc agtggtctta catgcacatc tcgggccagg acgcctcgga 18180gtacctgagc cccgggctgg tgcagtttgc ccgcgccacc gagacgtact tcagcctgaa 18240taacaagttt agaaacccca cggtggcgcc tacgcacgac gtgaccacag accggtccca 18300gcgtttgacg ctgcggttca tccctgtgga ccgtgaggat actgcgtact cgtacaaggc 18360gcggttcacc ctagctgtgg gtgataaccg tgtgctggac atggcttcca cgtactttga 18420catccgcggc gtgctggaca ggggccctac ttttaagccc tactctggca ctgcctacaa 18480cgccctggct cccaagggtg ccccaaatcc ttgcgaatgg gatgaagctg ctactgctct 18540tgaaataaac ctagaagaag aggacgatga caacgaagac gaagtagacg agcaagctga 18600gcagcaaaaa actcacgtat ttgggcaggc gccttattct ggtataaata ttacaaagga 18660gggtattcaa ataggtgtcg aaggtcaaac acctaaatat gccgataaaa catttcaacc 18720tgaacctcaa ataggagaat ctcagtggta cgaaacagaa attaatcatg cagctgggag 18780agtcctaaaa aagactaccc caatgaaacc atgttacggt tcatatgcaa aacccacaaa 18840tgaaaatgga gggcaaggca ttcttgtaaa gcaacaaaat ggaaagctag aaagtcaagt 18900ggaaatgcaa tttttctcaa ctactgaggc agccgcaggc aatggtgata acttgactcc 18960taaagtggta ttgtacagtg aagatgtaga tatagaaacc ccagacactc atatttctta 19020catgcccact attaaggaag gtaactcacg agaactaatg ggccaacaat ctatgcccaa 19080caggcctaat tacattgctt ttagggacaa ttttattggt ctaatgtatt acaacagcac 19140gggtaatatg ggtgttctgg cgggccaagc atcgcagttg aatgctgttg tagatttgca 19200agacagaaac acagagcttt cataccagct tttgcttgat tccattggtg atagaaccag 19260gtacttttct atgtggaatc aggctgttga cagctatgat ccagatgtta gaattattga 19320aaatcatgga actgaagatg aacttccaaa ttactgcttt ccactgggag gtgtgattaa 19380tacagagact cttaccaagg taaaacctaa aacaggtcag gaaaatggat gggaaaaaga 19440tgctacagaa ttttcagata aaaatgaaat aagagttgga aataattttg ccatggaaat 19500caatctaaat gccaacctgt ggagaaattt cctgtactcc aacatagcgc tgtatttgcc 19560cgacaagcta aagtacagtc cttccaacgt aaaaatttct gataacccaa acacctacga 19620ctacatgaac aagcgagtgg tggctcccgg gctagtggac tgctacatta accttggagc 19680acgctggtcc cttgactata tggacaacgt caacccattt aaccaccacc gcaatgctgg 19740cctgcgctac cgctcaatgt tgctgggcaa tggtcgctat gtgcccttcc acatccaggt 19800gcctcagaag ttctttgcca ttaaaaacct ccttctcctg ccgggctcat acacctacga 19860gtggaacttc aggaaggatg ttaacatggt tctgcagagc tccctaggaa atgacctaag 19920ggttgacgga gccagcatta agtttgatag catttgcctt tacgccacct tcttccccat 19980ggcccacaac accgcctcca cgcttgaggc catgcttaga aacgacacca acgaccagtc 20040ctttaacgac tatctctccg ccgccaacat gctctaccct atacccgcca acgctaccaa 20100cgtgcccata tccatcccct cccgcaactg ggcggctttc cgcggctggg ccttcacgcg 20160ccttaagact aaggaaaccc catcactggg ctcgggctac gacccttatt acacctactc 20220tggctctata ccctacctag atggaacctt ttacctcaac cacaccttta agaaggtggc 20280cattaccttt gactcttctg tcagctggcc tggcaatgac cgcctgctta cccccaacga 20340gtttgaaatt aagcgctcag ttgacgggga gggttacaac gttgcccagt gtaacatgac 20400caaagactgg ttcctggtac aaatgctagc taactataac attggctacc agggcttcta 20460tatcccagag agctacaagg accgcatgta ctccttcttt agaaacttcc agcccatgag 20520ccgtcaggtg gtggatgata ctaaatacaa ggactaccaa caggtgggca tcctacacca 20580acacaacaac tctggatttg ttggctacct tgcccccacc atgcgcgaag gacaggccta 20640ccctgctaac ttcccctatc cgcttatagg caagaccgca gttgacagca ttacccagaa 20700aaagtttctt tgcgatcgca ccctttggcg catcccattc tccagtaact ttatgtccat 20760gggcgcactc acagacctgg gccaaaacct tctctacgcc aactccgccc acgcgctaga 20820catgactttt gaggtggatc ccatggacga gcccaccctt ctttatgttt tgtttgaagt 20880ctttgacgtg gtccgtgtgc accagccgca ccgcggcgtc atcgaaaccg tgtacctgcg 20940cacgcccttc tcggccggca acgccacaac ataaagaagc aagcaacatc aacaacagct 21000gccgccatgg gctccagtga gcaggaactg aaagccattg tcaaagatct tggttgtggg 21060ccatattttt tgggcaccta tgacaagcgc tttccaggct ttgtttctcc acacaagctc 21120gcctgcgcca tagtcaatac ggccggtcgc gagactgggg gcgtacactg gatggccttt 21180gcctggaacc cgcactcaaa aacatgctac ctctttgagc cctttggctt ttctgaccag 21240cgactcaagc aggtttacca gtttgagtac gagtcactcc tgcgccgtag cgccattgct 21300tcttcccccg accgctgtat aacgctggaa aagtccaccc aaagcgtaca ggggcccaac 21360tcggccgcct gtggactatt ctgctgcatg tttctccacg cctttgccaa ctggccccaa 21420actcccatgg atcacaaccc caccatgaac cttattaccg gggtacccaa ctccatgctc 21480aacagtcccc aggtacagcc caccctgcgt cgcaaccagg aacagctcta cagcttcctg 21540gagcgccact cgccctactt ccgcagccac agtgcgcaga ttaggagcgc cacttctttt 21600tgtcacttga aaaacatgta aaaataatgt actagagaca ctttcaataa aggcaaatgc 21660ttttatttgt acactctcgg gtgattattt acccccaccc ttgccgtctg cgccgtttaa 21720aaatcaaagg ggttctgccg cgcatcgcta tgcgccactg gcagggacac gttgcgatac 21780tggtgtttag tgctccactt aaactcaggc acaaccatcc gcggcagctc ggtgaagttt 21840tcactccaca ggctgcgcac catcaccaac gcgtttagca ggtcgggcgc cgatatcttg 21900aagtcgcagt tggggcctcc gccctgcgcg cgcgagttgc gatacacagg gttgcagcac 21960tggaacacta tcagcgccgg gtggtgcacg ctggccagca cgctcttgtc ggagatcaga 22020tccgcgtcca ggtcctccgc gttgctcagg gcgaacggag tcaactttgg tagctgcctt 22080cccaaaaagg gcgcgtgccc aggctttgag ttgcactcgc accgtagtgg catcaaaagg 22140tgaccgtgcc cggtctgggc gttaggatac agcgcctgca taaaagcctt gatctgctta 22200aaagccacct gagcctttgc gccttcagag aagaacatgc cgcaagactt gccggaaaac 22260tgattggccg gacaggccgc gtcgtgcacg cagcaccttg cgtcggtgtt ggagatctgc 22320accacatttc ggccccaccg gttcttcacg atcttggcct tgctagactg ctccttcagc 22380gcgcgctgcc cgttttcgct cgtcacatcc atttcaatca cgtgctcctt atttatcata 22440atgcttccgt gtagacactt aagctcgcct tcgatctcag cgcagcggtg cagccacaac 22500gcgcagcccg tgggctcgtg atgcttgtag gtcacctctg caaacgactg caggtacgcc 22560tgcaggaatc gccccatcat cgtcacaaag gtcttgttgc tggtgaaggt cagctgcaac 22620ccgcggtgct cctcgttcag ccaggtcttg catacggccg ccagagcttc cacttggtca 22680ggcagtagtt tgaagttcgc ctttagatcg ttatccacgt ggtacttgtc catcagcgcg 22740cgcgcagcct ccatgccctt ctcccacgca gacacgatcg gcacactcag cgggttcatc 22800accgtaattt cactttccgc ttcgctgggc tcttcctctt cctcttgcgt ccgcatacca 22860cgcgccactg ggtcgtcttc attcagccgc cgcactgtgc gcttacctcc tttgccatgc 22920ttgattagca ccggtgggtt gctgaaaccc accatttgta gcgccacatc ttctctttct 22980tcctcgctgt ccacgattac ctctggtgat ggcgggcgct cgggcttggg agaagggcgc 23040ttctttttct tcttgggcgc aatggccaaa tccgccgccg aggtcgatgg ccgcgggctg 23100ggtgtgcgcg gcaccagcgc gtcttgtgat gagtcttcct cgtcctcgga ctcgatacgc 23160cgcctcatcc gcttttttgg gggcgcccgg ggaggcggcg gcgacgggga cggggacgac 23220acgtcctcca tggttggggg acgtcgcgcc gcaccgcgtc cgcgctcggg ggtggtttcg 23280cgctgctcct cttcccgact ggccatttcc ttctcctata ggcagaaaaa gatcatggag 23340tcagtcgaga agaaggacag cctaaccgcc ccctctgagt tcgccaccac cgcctccacc 23400gatgccgcca acgcgcctac caccttcccc gtcgaggcac ccccgcttga ggaggaggaa 23460gtgattatcg agcaggaccc aggttttgta agcgaagacg acgaggaccg ctcagtacca 23520acagaggata aaaagcaaga ccaggacaac gcagaggcaa acgaggaaca agtcgggcgg 23580ggggacgaaa ggcatggcga ctacctagat gtgggagacg acgtgctgtt gaagcatctg 23640cagcgccagt gcgccattat ctgcgacgcg ttgcaagagc gcagcgatgt gcccctcgcc 23700atagcggatg tcagccttgc ctacgaacgc cacctattct caccgcgcgt accccccaaa 23760cgccaagaaa acggcacatg cgagcccaac ccgcgcctca acttctaccc cgtatttgcc 23820gtgccagagg tgcttgccac ctatcacatc tttttccaaa actgcaagat acccctatcc 23880tgccgtgcca accgcagccg agcggacaag cagctggcct tgcggcaggg cgctgtcata 23940cctgatatcg cctcgctcaa cgaagtgcca aaaatctttg agggtcttgg acgcgacgag 24000aagcgcgcgg caaacgctct gcaacaggaa aacagcgaaa atgaaagtca ctctggagtg 24060ttggtggaac tcgagggtga caacgcgcgc ctagccgtac taaaacgcag catcgaggtc 24120acccactttg cctacccggc acttaaccta ccccccaagg tcatgagcac agtcatgagt 24180gagctgatcg tgcgccgtgc gcagcccctg gagagggatg caaatttgca agaacaaaca 24240gaggagggcc tacccgcagt tggcgacgag cagctagcgc gctggcttca aacgcgcgag 24300cctgccgact tggaggagcg acgcaaacta atgatggccg cagtgctcgt taccgtggag 24360cttgagtgca tgcagcggtt ctttgctgac ccggagatgc agcgcaagct agaggaaaca 24420ttgcactaca cctttcgaca gggctacgta cgccaggcct gcaagatctc caacgtggag 24480ctctgcaacc tggtctccta ccttggaatt ttgcacgaaa accgccttgg gcaaaacgtg 24540cttcattcca cgctcaaggg cgaggcgcgc cgcgactacg tccgcgactg cgtttactta 24600tttctatgct acacctggca gacggccatg ggcgtttggc agcagtgctt ggaggagtgc 24660aacctcaagg agctgcagaa actgctaaag caaaacttga aggacctatg gacggccttc 24720aacgagcgct ccgtggccgc gcacctggcg gacatcattt tccccgaacg cctgcttaaa 24780accctgcaac agggtctgcc agacttcacc agtcaaagca tgttgcagaa ctttaggaac 24840tttatcctag agcgctcagg aatcttgccc gccacctgct gtgcacttcc tagcgacttt 24900gtgcccatta agtaccgcga atgccctccg ccgctttggg gccactgcta ccttctgcag 24960ctagccaact accttgccta ccactctgac ataatggaag acgtgagcgg tgacggtcta 25020ctggagtgtc actgtcgctg caacctatgc accccgcacc gctccctggt ttgcaattcg 25080cagctgctta acgaaagtca aattatcggt acctttgagc tgcagggtcc ctcgcctgac 25140gaaaagtccg cggctccggg gttgaaactc actccggggc tgtggacgtc ggcttacctt 25200cgcaaatttg tacctgagga ctaccacgcc cacgagatta ggttctacga agaccaatcc 25260cgcccgccta atgcggagct taccgcctgc gtcattaccc agggccacat tcttggccaa 25320ttgcaagcca tcaacaaagc ccgccaagag tttctgctac gaaagggacg gggggtttac 25380ttggaccccc agtccggcga ggagctcaac ccaatccccc cgccgccgca gccctatcag 25440cagcagccgc gggcccttgc ttcccaggat ggcacccaaa aagaagctgc agctgccgcc 25500gccacccacg gacgaggagg aatactggga cagtcaggca gaggaggttt tggacgagga 25560ggaggaggac atgatggaag actgggagag cctagacgag gaagcttccg aggtcgaaga 25620ggtgtcagac gaaacaccgt caccctcggt cgcattcccc tcgccggcgc cccagaaatc 25680ggcaaccggt tccagcatgg ctacaacctc cgctcctcag gcgccgccgg cactgcccgt 25740tcgccgaccc aaccgtagat gggacaccac tggaaccagg gccggtaagt ccaagcagcc 25800gccgccgtta gcccaagagc aacaacagcg ccaaggctac cgctcatggc gcgggcacaa 25860gaacgccata gttgcttgct tgcaagactg tgggggcaac atctccttcg cccgccgctt 25920tcttctctac catcacggcg tggccttccc ccgtaacatc ctgcattact accgtcatct 25980ctacagccca tactgcaccg gcggcagcgg cagcaacagc agcggccaca cagaagcaaa 26040ggcgaccgga tagcaagact ctgacaaagc ccaagaaatc cacagcggcg gcagcagcag 26100gaggaggagc gctgcgtctg gcgcccaacg aacccgtatc gacccgcgag cttagaaaca 26160ggatttttcc cactctgtat gctatatttc aacagagcag gggccaagaa caagagctga 26220aaataaaaaa caggtctctg cgatccctca cccgcagctg cctgtatcac aaaagcgaag 26280atcagcttcg gcgcacgctg gaagacgcgg aggctctctt cagtaaatac tgcgcgctga 26340ctcttaagga ctagtttcgc gccctttctc aaatttaagc gcgaaaacta cgtcatctcc 26400agcggccaca cccggcgcca gcacctgttg tcagcgccat tatgagcaag gaaattccca 26460cgccctacat gtggagttac cagccacaaa tgggacttgc ggctggagct gcccaagact 26520actcaacccg aataaactac atgagcgcgg gaccccacat gatatcccgg gtcaacggaa 26580tacgcgccca ccgaaaccga attctcctgg aacaggcggc tattaccacc acacctcgta 26640ataaccttaa tccccgtagt tggcccgctg ccctggtgta ccaggaaagt cccgctccca 26700ccactgtggt acttcccaga gacgcccagg ccgaagttca gatgactaac tcaggggcgc 26760agcttgcggg cggctttcgt cacagggtgc ggtcgcccgg gcagggtata actcacctga 26820caatcagagg gcgaggtatt cagctcaacg acgagtcggt gagctcctcg cttggtctcc 26880gtccggacgg gacatttcag atcggcggcg ccggccgctc ttcattcacg cctcgtcagg 26940caatcctaac tctgcagacc tcgtcctctg agccgcgctc tggaggcatt ggaactctgc 27000aatttattga ggagtttgtg ccatcggtct actttaaccc cttctcggga cctcccggcc 27060actatccgga tcaatttatt cctaactttg acgcggtaaa ggactcggcg gacggctacg 27120actgaatgtt aagtggagag gcagagcaac tgcgcctgaa acacctggtc cactgtcgcc 27180gccacaagtg ctttgcccgc gactccggtg agttttgcta ctttgaattg cccgaggatc 27240atatcgaggg cccggcgcac ggcgtccggc ttaccgccca gggagagctt gcccgtagcc 27300tgattcggga gtttacccag cgccccctgc tagttgagcg ggacagggga ccctgtgttc 27360tcactgtgat ttgcaactgt cctaaccctg gattacatca agatctttgt tgccatctct 27420gtgctgagta taataaatac agaaattaaa atatactggg gctcctatcg ccatcctgta 27480aacgccaccg tcttcacccg cccaagcaaa ccaaggcgaa ccttacctgg tacttttaac 27540atctctccct ctgtgattta caacagtttc aacccagacg gagtgagtct acgagagaac 27600ctctccgagc tcagctactc catcagaaaa aacaccaccc tccttacctg ccgggaacgt 27660acgagtgcgt caccggccgc tgcaccacac ctaccgcctg accgtaaacc agactttttc 27720cggacagacc tcaataactc tgtttaccag aacaggaggt gagcttagaa aacccttagg 27780gtattaggcc aaaggcgcag ctactgtggg gtttatgaac aattcaagca actctacggg 27840ctattctaat tcaggtttct ctagaatcgg ggttggggtt attctctgtc ttgtgattct 27900ctttattctt atactaacgc ttctctgcct aaggctcgcc gcctgctgtg tgcacatttg 27960catttattgt cagcttttta aacgctgggg tcgccaccca agatgattag gtacataatc 28020ctaggtttac tcacccttgc gtcagcccac ggtaccaccc aaaaggtgga ttttaaggag 28080ccagcctgta atgttacatt cgcagctgaa gctaatgagt gcaccactct tataaaatgc 28140accacagaac atgaaaagct gcttattcgc cacaaaaaca aaattggcaa gtatgctgtt 28200tatgctattt ggcagccagg tgacactaca gagtataatg ttacagtttt ccagggtaaa 28260agtcataaaa cttttatgta tacttttcca ttttatgaaa tgtgcgacat taccatgtac 28320atgagcaaac agtataagtt gtggccccca caaaattgtg tggaaaacac tggcactttc 28380tgctgcactg ctatgctaat tacagtgctc gctttggtct gtaccctact ctatattaaa 28440tacaaaagca gacgcagctt tattgaggaa aagaaaatgc cttaatttac taagttacaa 28500agctaatgtc accactaact gctttactcg ctgcttgcaa aacaaattca aaaagttagc 28560attataatta gaataggatt taaacccccc ggtcatttcc tgctcaatac cattcccctg 28620aacaattgac tctatgtggg atatgctcca gcgctacaac cttgaagtca ggcttcctgg 28680atgtcagcat ctgactttgg ccagcacctg tcccgcggat ttgttccagt ccaactacag 28740cgacccaccc taacagagat gaccaacaca accaacgcgg ccgccgctac cggacttaca 28800tctaccacaa atacacccca agtttctgcc tttgtcaata actgggataa cttgggcatg 28860tggtggttct ccatagcgct tatgtttgta tgccttatta ttatgtggct catctgctgc 28920ctaaagcgca aacgcgcccg accacccatc tatagtccca tcattgtgct acacccaaac 28980aatgatggaa tccatagatt ggacggactg aaacacatgt tcttttctct tacagtatga 29040ttaaatgaga catgattcct cgagttttta tattactgac ccttgttgcg ctttttttgt 29100gcgtgctcca cattggctgc ggtttctcac atcgaagtag actgcattcc agccttcaca 29160gtctatttgc tttacggatt tgtcaccctc acgctcatct gcagcctcat cactgtggtc 29220atcgccttta tccagtgcat tgactgggtc tgtgtgcgct ttgcatatct cagacaccat 29280ccccagtaca gggacaggac tatagctgag cttcttagaa ttctttaatt atgaaattta 29340ctgtgacttt tctgctgatt atttgcaccc tatctgcgtt ttgttccccg acctccaagc 29400ctcaaagaca tatatcatgc agattcactc gtatatggaa tattccaagt tgctacaatg 29460aaaaaagcga tctttccgaa gcctggttat atgcaatcat ctctgttatg gtgttctgca 29520gtaccatctt agccctagct atatatccct accttgacat tggctggaac gcaatagatg 29580ccatgaacca cccaactttc cccgcgcccg ctatgcttcc actgcaacaa gttgttgccg 29640gcggctttgt cccagccaat cagcctcgcc caccttctcc cacccccact gaaatcagct 29700actttaatct aacaggagga gatgactgac accctagatc tagaaatgga cggaattatt 29760acagagcagc gcctgctaga aagacgcagg gcagcggccg agcaacagcg catgaatcaa 29820gagctccaag acatggttaa cttgcaccag tgcaaaaggg gtatcttttg tctggtaaag 29880caggccaaag tcacctacga cagtaatacc accggacacc gccttagcta caagttgcca 29940accaagcgtc agaaattggt ggtcatggtg ggagaaaagc ccattaccat aactcagcac 30000tcggtagaaa ccgaaggctg cattcactca ccttgtcaag gacctgagga tctctgcacc 30060cttattaaga ccctgtgcgg tctcaaagat cttattccct ttaactaata aaaaaaaata 30120ataaagcatc acttacttaa aatcagttag caaatttctg tccagtttat tcagcagcac 30180ctccttgccc tcctcccagc tctggtattg cagcttcctc ctggctgcaa actttctcca 30240caatctaaat ggaatgtcag tttcctcctg ttcctgtcca tccgcaccca ctatcttcat 30300gttgttgcag atgaagcgcg caagaccgtc tgaagatacc ttcaaccccg tgtatccata 30360tgacacggaa accggtcctc caactgtgcc ttttcttact cctccctttg tatcccccaa 30420tgggtttcaa gagagtcccc ctggggtact ctctttgcgc ctatccgaac ctctagttac 30480ctccaatggc atgcttgcgc tcaaaatggg caacggcctc tctctggacg aggccggcaa 30540ccttacctcc caaaatgtaa ccactgtgag cccacctctc aaaaaaacca agtcaaacat 30600aaacctggaa atatctgcac ccctcacagt tacctcagaa gccctaactg tggctgccgc 30660cgcacctcta atggtcgcgg gcaacacact caccatgcaa tcacaggccc cgctaaccgt 30720gcacgactcc aaacttagca ttgccaccca aggacccctc acagtgtcag aaggaaagct 30780agccctgcaa acatcaggcc ccctcaccac caccgatagc agtaccctta ctatcactgc 30840ctcaccccct ctaactactg ccactggtag cttgggcatt gacttgaaag agcccattta 30900tacacaaaat ggaaaactag gactaaagta cggggctcct ttgcatgtaa cagacgacct 30960aaacactttg accgtagcaa ctggtccagg tgtgactatt aataatactt ccttgcaaac 31020taaagttact ggagccttgg gttttgattc acaaggcaat atgcaactta atgtagcagg 31080aggactaagg attgattctc aaaacagacg ccttatactt gatgttagtt atccgtttga 31140tgctcaaaac caactaaatc taagactagg acagggccct ctttttataa actcagccca 31200caacttggat attaactaca acaaaggcct ttacttgttt acagcttcaa acaattccaa 31260aaagcttgag

gttaacctaa gcactgccaa ggggttgatg tttgacgcta cagccatagc 31320cattaatgca ggagatgggc ttgaatttgg ttcacctaat gcaccaaaca caaatcccct 31380caaaacaaaa attggccatg gcctagaatt tgattcaaac aaggctatgg ttcctaaact 31440aggaactggc cttagttttg acagcacagg tgccattaca gtaggaaaca aaaataatga 31500taagctaact ttgtggacca caccagctcc atctcctaac tgtagactaa atgcagagaa 31560agatgctaaa ctcactttgg tcttaacaaa atgtggcagt caaatacttg ctacagtttc 31620agttttggct gttaaaggca gtttggctcc aatatctgga acagttcaaa gtgctcatct 31680tattataaga tttgacgaaa atggagtgct actaaacaat tccttcctgg acccagaata 31740ttggaacttt agaaatggag atcttactga aggcacagcc tatacaaacg ctgttggatt 31800tatgcctaac ctatcagctt atccaaaatc tcacggtaaa actgccaaaa gtaacattgt 31860cagtcaagtt tacttaaacg gagacaaaac taaacctgta acactaacca ttacactaaa 31920cggtacacag gaaacaggag acacaactcc aagtgcatac tctatgtcat tttcatggga 31980ctggtctggc cacaactaca ttaatgaaat atttgccaca tcctcttaca ctttttcata 32040cattgcccaa gaataaagaa tcgtttgtgt tatgtttcaa cgtgtttatt tttcaattgc 32100agaaaatttc aagtcatttt tcattcagta gtatagcccc accaccacat agcttataca 32160gatcaccgta ccttaatcaa actcacagaa ccctagtatt caacctgcca cctccctccc 32220aacacacaga gtacacagtc ctttctcccc ggctggcctt aaaaagcatc atatcatggg 32280taacagacat attcttaggt gttatattcc acacggtttc ctgtcgagcc aaacgctcat 32340cagtgatatt aataaactcc ccgggcagct cacttaagtt catgtcgctg tccagctgct 32400gagccacagg ctgctgtcca acttgcggtt gcttaacggg cggcgaagga gaagtccacg 32460cctacatggg ggtagagtca taatcgtgca tcaggatagg gcggtggtgc tgcagcagcg 32520cgcgaataaa ctgctgccgc cgccgctccg tcctgcagga atacaacatg gcagtggtct 32580cctcagcgat gattcgcacc gcccgcagca taaggcgcct tgtcctccgg gcacagcagc 32640gcaccctgat ctcacttaaa tcagcacagt aactgcagca cagcaccaca atattgttca 32700aaatcccaca gtgcaaggcg ctgtatccaa agctcatggc ggggaccaca gaacccacgt 32760ggccatcata ccacaagcgc aggtagatta agtggcgacc cctcataaac acgctggaca 32820taaacattac ctcttttggc atgttgtaat tcaccacctc ccggtaccat ataaacctct 32880gattaaacat ggcgccatcc accaccatcc taaaccagct ggccaaaacc tgcccgccgg 32940ctatacactg cagggaaccg ggactggaac aatgacagtg gagagcccag gactcgtaac 33000catggatcat catgctcgtc atgatatcaa tgttggcaca acacaggcac acgtgcatac 33060acttcctcag gattacaagc tcctcccgcg ttagaaccat atcccaggga acaacccatt 33120cctgaatcag cgtaaatccc acactgcagg gaagacctcg cacgtaactc acgttgtgca 33180ttgtcaaagt gttacattcg ggcagcagcg gatgatcctc cagtatggta gcgcgggttt 33240ctgtctcaaa aggaggtaga cgatccctac tgtacggagt gcgccgagac aaccgagatc 33300gtgttggtcg tagtgtcatg ccaaatggaa cgccggacgt agtcatattt cctgaagcaa 33360aaccaggtgc gggcgtgaca aacagatctg cgtctccggt ctcgccgctt agatcgctct 33420gtgtagtagt tgtagtatat ccactctctc aaagcatcca ggcgccccct ggcttcgggt 33480tctatgtaaa ctccttcatg cgccgctgcc ctgataacat ccaccaccgc agaataagcc 33540acacccagcc aacctacaca ttcgttctgc gagtcacaca cgggaggagc gggaagagct 33600ggaagaacca tgtttttttt tttattccaa aagattatcc aaaacctcaa aatgaagatc 33660tattaagtga acgcgctccc ctccggtggc gtggtcaaac tctacagcca aagaacagat 33720aatggcattt gtaagatgtt gcacaatggc ttccaaaagg caaacggccc tcacgtccaa 33780gtggacgtaa aggctaaacc cttcagggtg aatctcctct ataaacattc cagcaccttc 33840aaccatgccc aaataattct catctcgcca ccttctcaat atatctctaa gcaaatcccg 33900aatattaagt ccggccattg taaaaatctg ctccagagcg ccctccacct tcagcctcaa 33960gcagcgaatc atgattgcaa aaattcaggt tcctcacaga cctgtataag attcaaaagc 34020ggaacattaa caaaaatacc gcgatcccgt aggtcccttc gcagggccag ctgaacataa 34080tcgtgcaggt ctgcacggac cagcgcggcc acttccccgc caggaaccat gacaaaagaa 34140cccacactga ttatgacacg catactcgga gctatgctaa ccagcgtagc cccgatgtaa 34200gcttgttgca tgggcggcga tataaaatgc aaggtgctgc tcaaaaaatc aggcaaagcc 34260tcgcgcaaaa aagaaagcac atcgtagtca tgctcatgca gataaaggca ggtaagctcc 34320ggaaccacca cagaaaaaga caccattttt ctctcaaaca tgtctgcggg tttctgcata 34380aacacaaaat aaaataacaa aaaaacattt aaacattaga agcctgtctt acaacaggaa 34440aaacaaccct tataagcata agacggacta cggccatgcc ggcgtgaccg taaaaaaact 34500ggtcaccgtg attaaaaagc accaccgaca gctcctcggt catgtccgga gtcataatgt 34560aagactcggt aaacacatca ggttgattca catcggtcag tgctaaaaag cgaccgaaat 34620agcccggggg aatacatacc cgcaggcgta gagacaacat tacagccccc ataggaggta 34680taacaaaatt aataggagag aaaaacacat aaacacctga aaaaccctcc tgcctaggca 34740aaatagcacc ctcccgctcc agaacaacat acagcgcttc cacagcggca gccataacag 34800tcagccttac cagtaaaaaa gaaaacctat taaaaaaaca ccactcgaca cggcaccagc 34860tcaatcagtc acagtgtaaa aaagggccaa gtgcagagcg agtatatata ggactaaaaa 34920atgacgtaac ggttaaagtc cacaaaaaac acccagaaaa ccgcacgcga acctacgccc 34980agaaacgaaa gccaaaaaac ccacaacttc ctcaaatcgt cacttccgtt ttcccacgtt 35040acgtcacttc ccattttaag aaaactacaa ttcccaacac atacaagtta ctccgcccta 35100aaacctacgt cacccgcccc gttcccacgc cccgcgccac gtcacaaact ccaccccctc 35160attatcatat tggcttcaat ccaaaataag gtatattatt gat 352031133093DNAArtificial sequenceEmpty Ad5 vector sequence (repeats included) 11catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420cgggtcaaag ttggcgtttt attattatag tcagtacgtc tcgagcatgc atctaggcgg 480ccgcatggca gaaattcgcg aattcgctag cgttaacgga tcctctagac gagatccgaa 540cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa atttcacaaa 600taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca atgtatctta 660tcatgtctag atctgtactg aaatgtgtgg gcgtggctta agggtgggaa agaatatata 720aggtgggggt cttatgtagt tttgtatctg ttttgcagca gccgccgccg ccatgagcac 780caactcgttt gatggaagca ttgtgagctc atatttgaca acgcgcatgc ccccatgggc 840cggggtgcgt cagaatgtga tgggctccag cattgatggt cgccccgtcc tgcccgcaaa 900ctctactacc ttgacctacg agaccgtgtc tggaacgccg ttggagactg cagcctccgc 960cgccgcttca gccgctgcag ccaccgcccg cgggattgtg actgactttg ctttcctgag 1020cccgcttgca agcagtgcag cttcccgttc atccgcccgc gatgacaagt tgacggctct 1080tttggcacaa ttggattctt tgacccggga acttaatgtc gtttctcagc agctgttgga 1140tctgcgccag caggtttctg ccctgaaggc ttcctcccct cccaatgcgg tttaaaacat 1200aaataaaaaa ccagactctg tttggatttg gatcaagcaa gtgtcttgct gtctttattt 1260aggggttttg cgcgcgcggt aggcccggga ccagcggtct cggtcgttga gggtcctgtg 1320tattttttcc aggacgtggt aaaggtgact ctggatgttc agatacatgg gcataagccc 1380gtctctgggg tggaggtagc accactgcag agcttcatgc tgcggggtgg tgttgtagat 1440gatccagtcg tagcaggagc gctgggcgtg gtgcctaaaa atgtctttca gtagcaagct 1500gattgccagg ggcaggccct tggtgtaagt gtttacaaag cggttaagct gggatgggtg 1560catacgtggg gatatgagat gcatcttgga ctgtattttt aggttggcta tgttcccagc 1620catatccctc cggggattca tgttgtgcag aaccaccagc acagtgtatc cggtgcactt 1680gggaaatttg tcatgtagct tagaaggaaa tgcgtggaag aacttggaga cgcccttgtg 1740acctccaaga ttttccatgc attcgtccat aatgatggca atgggcccac gggcggcggc 1800ctgggcgaag atatttctgg gatcactaac gtcatagttg tgttccagga tgagatcgtc 1860ataggccatt tttacaaagc gcgggcggag ggtgccagac tgcggtataa tggttccatc 1920cggcccaggg gcgtagttac cctcacagat ttgcatttcc cacgctttga gttcagatgg 1980ggggatcatg tctacctgcg gggcgatgaa gaaaacggtt tccggggtag gggagatcag 2040ctgggaagaa agcaggttcc tgagcagctg cgacttaccg cagccggtgg gcccgtaaat 2100cacacctatt accggctgca actggtagtt aagagagctg cagctgccgt catccctgag 2160caggggggcc acttcgttaa gcatgtccct gactcgcatg ttttccctga ccaaatccgc 2220cagaaggcgc tcgccgccca gcgatagcag ttcttgcaag gaagcaaagt ttttcaacgg 2280tttgagaccg tccgccgtag gcatgctttt gagcgtttga ccaagcagtt ccaggcggtc 2340ccacagctcg gtcacctgct ctacggcatc tcgatccagc atatctcctc gtttcgcggg 2400ttggggcggc tttcgctgta cggcagtagt cggtgctcgt ccagacgggc cagggtcatg 2460tctttccacg ggcgcagggt cctcgtcagc gtagtctggg tcacggtgaa ggggtgcgct 2520ccgggctgcg cgctggccag ggtgcgcttg aggctggtcc tgctggtgct gaagcgctgc 2580cggtcttcgc cctgcgcgtc ggccaggtag catttgacca tggtgtcata gtccagcccc 2640tccgcggcgt ggcccttggc gcgcagcttg cccttggagg aggcgccgca cgaggggcag 2700tgcagacttt tgagggcgta gagcttgggc gcgagaaata ccgattccgg ggagtaggca 2760tccgcgccgc aggccccgca gacggtctcg cattccacga gccaggtgag ctctggccgt 2820tcggggtcaa aaaccaggtt tcccccatgc tttttgatgc gtttcttacc tctggtttcc 2880atgagccggt gtccacgctc ggtgacgaaa aggctgtccg tgtccccgta tacagacttg 2940agaggcctgt cctcgagcgg tgttccgcgg tcctcctcgt atagaaactc ggaccactct 3000gagacaaagg ctcgcgtcca ggccagcacg aaggaggcta agtgggaggg gtagcggtcg 3060ttgtccacta gggggtccac tcgctccagg gtgtgaagac acatgtcgcc ctcttcggca 3120tcaaggaagg tgattggttt gtaggtgtag gccacgtgac cgggtgttcc tgaagggggg 3180ctataaaagg gggtgggggc gcgttcgtcc tcactctctt ccgcatcgct gtctgcgagg 3240gccagctgtt ggggtgagta ctccctctga aaagcgggca tgacttctgc gctaagattg 3300tcagtttcca aaaacgagga ggatttgata ttcacctggc ccgcggtgat gcctttgagg 3360gtggccgcat ccatctggtc agaaaagaca atctttttgt tgtcaagctt ggtggcaaac 3420gacccgtaga gggcgttgga cagcaacttg gcgatggagc gcagggtttg gtttttgtcg 3480cgatcggcgc gctccttggc cgcgatgttt agctgcacgt attcgcgcgc aacgcaccgc 3540cattcgggaa agacggtggt gcgctcgtcg ggcaccaggt gcacgcgcca accgcggttg 3600tgcagggtga caaggtcaac gctggtggct acctctccgc gtaggcgctc gttggtccag 3660cagaggcggc cgcccttgcg cgagcagaat ggcggtaggg ggtctagctg cgtctcgtcc 3720ggggggtctg cgtccacggt aaagaccccg ggcagcaggc gcgcgtcgaa gtagtctatc 3780ttgcatcctt gcaagtctag cgcctgctgc catgcgcggg cggcaagcgc gcgctcgtat 3840gggttgagtg ggggacccca tggcatgggg tgggtgagcg cggaggcgta catgccgcaa 3900atgtcgtaaa cgtagagggg ctctctgagt attccaagat atgtagggta gcatcttcca 3960ccgcggatgc tggcgcgcac gtaatcgtat agttcgtgcg agggagcgag gaggtcggga 4020ccgaggttgc tacgggcggg ctgctctgct cggaagacta tctgcctgaa gatggcatgt 4080gagttggatg atatggttgg acgctggaag acgttgaagc tggcgtctgt gagacctacc 4140gcgtcacgca cgaaggaggc gtaggagtcg cgcagcttgt tgaccagctc ggcggtgacc 4200tgcacgtcta gggcgcagta gtccagggtt tccttgatga tgtcatactt atcctgtccc 4260ttttttttcc acagctcgcg gttgaggaca aactcttcgc ggtctttcca gtactcttgg 4320atcggaaacc cgtcggcctc cgaacggtaa gagcctagca tgtagaactg gttgacggcc 4380tggtaggcgc agcatccctt ttctacgggt agcgcgtatg cctgcgcggc cttccggagc 4440gaggtgtggg tgagcgcaaa ggtgtccctg accatgactt tgaggtactg gtatttgaag 4500tcagtgtcgt cgcatccgcc ctgctcccag agcaaaaagt ccgtgcgctt tttggaacgc 4560ggatttggca gggcgaaggt gacatcgttg aagagtatct ttcccgcgcg aggcataaag 4620ttgcgtgtga tgcggaaggg tcccggcacc tcggaacggt tgttaattac ctgggcggcg 4680agcacgatct cgtcaaagcc gttgatgttg tggcccacaa tgtaaagttc caagaagcgc 4740gggatgccct tgatggaagg caatttttta agttcctcgt aggtgagctc ttcaggggag 4800ctgagcccgt gctctgaaag ggcccagtct gcaagatgag ggttggaagc gacgaatgag 4860ctccacaggt cacgggccat tagcatttgc aggtggtcgc gaaaggtcct aaactggcga 4920cctatggcca ttttttctgg ggtgatgcag tagaaggtaa gcgggtcttg ttcccagcgg 4980tcccatccaa ggttcgcggc taggtctcgc gcggcagtca ctagaggctc atctccgccg 5040aacttcatga ccagcatgaa gggcacgagc tgcttcccaa aggcccccat ccaagtatag 5100gtctctacat cgtaggtgac aaagagacgc tcggtgcgag gatgcgagcc gatcgggaag 5160aactggatct cccgccacca attggaggag tggctattga tgtggtgaaa gtagaagtcc 5220ctgcgacggg ccgaacactc gtgctggctt ttgtaaaaac gtgcgcagta ctggcagcgg 5280tgcacgggct gtacatcctg cacgaggttg acctgacgac cgcgcacaag gaagcagagt 5340gggaatttga gcccctcgcc tggcgggttt ggctggtggt cttctacttc ggctgcttgt 5400ccttgaccgt ctggctgctc gaggggagtt acggtggatc ggaccaccac gccgcgcgag 5460cccaaagtcc agatgtccgc gcgcggcggt cggagcttga tgacaacatc gcgcagatgg 5520gagctgtcca tggtctggag ctcccgcggc gtcaggtcag gcgggagctc ctgcaggttt 5580acctcgcata gacgggtcag ggcgcgggct agatccaggt gatacctaat ttccaggggc 5640tggttggtgg cggcgtcgat ggcttgcaag aggccgcatc cccgcggcgc gactacggta 5700ccgcgcggcg ggcggtgggc cgcgggggtg tccttggatg atgcatctaa aagcggtgac 5760gcgggcgagc ccccggaggt agggggggct ccggacccgc cgggagaggg ggcaggggca 5820cgtcggcgcc gcgcgcgggc aggagctggt gctgcgcgcg taggttgctg gcgaacgcga 5880cgacgcggcg gttgatctcc tgaatctggc gcctctgcgt gaagacgacg ggcccggtga 5940gcttgaacct gaaagagagt tcgacagaat caatttcggt gtcgttgacg gcggcctggc 6000gcaaaatctc ctgcacgtct cctgagttgt cttgataggc gatctcggcc atgaactgct 6060cgatctcttc ctcctggaga tctccgcgtc cggctcgctc cacggtggcg gcgaggtcgt 6120tggaaatgcg ggccatgagc tgcgagaagg cgttgaggcc tccctcgttc cagacgcggc 6180tgtagaccac gcccccttcg gcatcgcggg cgcgcatgac cacctgcgcg agattgagct 6240ccacgtgccg ggcgaagacg gcgtagtttc gcaggcgctg aaagaggtag ttgagggtgg 6300tggcggtgtg ttctgccacg aagaagtaca taacccagcg tcgcaacgtg gattcgttga 6360tatcccccaa ggcctcaagg cgctccatgg cctcgtagaa gtccacggcg aagttgaaaa 6420actgggagtt gcgcgccgac acggttaact cctcctccag aagacggatg agctcggcga 6480cagtgtcgcg cacctcgcgc tcaaaggcta caggggcctc ttcttcttct tcaatctcct 6540cttccataag ggcctcccct tcttcttctt ctggcggcgg tgggggaggg gggacacggc 6600ggcgacgacg gcgcaccggg aggcggtcga caaagcgctc gatcatctcc ccgcggcgac 6660ggcgcatggt ctcggtgacg gcgcggccgt tctcgcgggg gcgcagttgg aagacgccgc 6720ccgtcatgtc ccggttatgg gttggcgggg ggctgccatg cggcagggat acggcgctaa 6780cgatgcatct caacaattgt tgtgtaggta ctccgccgcc gagggacctg agcgagtccg 6840catcgaccgg atcggaaaac ctctcgagaa aggcgtctaa ccagtcacag tcgcaaggta 6900ggctgagcac cgtggcgggc ggcagcgggc ggcggtcggg gttgtttctg gcggaggtgc 6960tgctgatgat gtaattaaag taggcggtct tgagacggcg gatggtcgac agaagcacca 7020tgtccttggg tccggcctgc tgaatgcgca ggcggtcggc catgccccag gcttcgtttt 7080gacatcggcg caggtctttg tagtagtctt gcatgagcct ttctaccggc acttcttctt 7140ctccttcctc ttgtcctgca tctcttgcat ctatcgctgc ggcggcggcg gagtttggcc 7200gtaggtggcg ccctcttcct cccatgcgtg tgaccccgaa gcccctcatc ggctgaagca 7260gggctaggtc ggcgacaacg cgctcggcta atatggcctg ctgcacctgc gtgagggtag 7320actggaagtc atccatgtcc acaaagcggt ggtatgcgcc cgtgttgatg gtgtaagtgc 7380agttggccat aacggaccag ttaacggtct ggtgacccgg ctgcgagagc tcggtgtacc 7440tgagacgcga gtaagccctc gagtcaaata cgtagtcgtt gcaagtccgc accaggtact 7500ggtatcccac caaaaagtgc ggcggcggct ggcggtagag gggccagcgt agggtggccg 7560gggctccggg ggcgagatct tccaacataa ggcgatgata tccgtagatg tacctggaca 7620tccaggtgat gccggcggcg gtggtggagg cgcgcggaaa gtcgcggacg cggttccaga 7680tgttgcgcag cggcaaaaag tgctccatgg tcgggacgct ctggccggtc aggcgcgcgc 7740aatcgttgac gctctagacc gtgcaaaagg agagcctgta agcgggcact cttccgtggt 7800ctggtggata aattcgcaag ggtatcatgg cggacgaccg gggttcgagc cccgtatccg 7860gccgtccgcc gtgatccatg cggttaccgc ccgcgtgtcg aacccaggtg tgcgacgtca 7920gacaacgggg gagtgctcct tttggcttcc ttccaggcgc ggcggctgct gcgctagctt 7980ttttggccac tggccgcgcg cagcgtaagc ggttaggctg gaaagcgaaa gcattaagtg 8040gctcgctccc tgtagccgga gggttatttt ccaagggttg agtcgcggga cccccggttc 8100gagtctcgga ccggccggac tgcggcgaac gggggtttgc ctccccgtca tgcaagaccc 8160cgcttgcaaa ttcctccgga aacagggacg agcccctttt ttgcttttcc cagatgcatc 8220cggtgctgcg gcagatgcgc ccccctcctc agcagcggca agagcaagag cagcggcaga 8280catgcagggc accctcccct cctcctaccg cgtcaggagg ggcgacatcc gcggttgacg 8340cggcagcaga tggtgattac gaacccccgc ggcgccgggc ccggcactac ctggacttgg 8400aggagggcga gggcctggcg cggctaggag cgccctctcc tgagcggcac ccaagggtgc 8460agctgaagcg tgatacgcgt gaggcgtacg tgccgcggca gaacctgttt cgcgaccgcg 8520agggagagga gcccgaggag atgcgggatc gaaagttcca cgcagggcgc gagctgcggc 8580atggcctgaa tcgcgagcgg ttgctgcgcg aggaggactt tgagcccgac gcgcgaaccg 8640ggattagtcc cgcgcgcgca cacgtggcgg ccgccgacct ggtaaccgca tacgagcaga 8700cggtgaacca ggagattaac tttcaaaaaa gctttaacaa ccacgtgcgt acgcttgtgg 8760cgcgcgagga ggtggctata ggactgatgc atctgtggga ctttgtaagc gcgctggagc 8820aaaacccaaa tagcaagccg ctcatggcgc agctgttcct tatagtgcag cacagcaggg 8880acaacgaggc attcagggat gcgctgctaa acatagtaga gcccgagggc cgctggctgc 8940tcgatttgat aaacatcctg cagagcatag tggtgcagga gcgcagcttg agcctggctg 9000acaaggtggc cgccatcaac tattccatgc ttagcctggg caagttttac gcccgcaaga 9060tataccatac cccttacgtt cccatagaca aggaggtaaa gatcgagggg ttctacatgc 9120gcatggcgct gaaggtgctt accttgagcg acgacctggg cgtttatcgc aacgagcgca 9180tccacaaggc cgtgagcgtg agccggcggc gcgagctcag cgaccgcgag ctgatgcaca 9240gcctgcaaag ggccctggct ggcacgggca gcggcgatag agaggccgag tcctactttg 9300acgcgggcgc tgacctgcgc tgggccccaa gccgacgcgc cctggaggca gctggggccg 9360gacctgggct ggcggtggca cccgcgcgcg ctggcaacgt cggcggcgtg gaggaatatg 9420acgaggacga tgagtacgag ccagaggacg gcgagtacta agcggtgatg tttctgatca 9480gatgatgcaa gacgcaacgg acccggcggt gcgggcggcg ctgcagagcc agccgtccgg 9540ccttaactcc acggacgact ggcgccaggt catggaccgc atcatgtcgc tgactgcgcg 9600caatcctgac gcgttccggc agcagccgca ggccaaccgg ctctccgcaa ttctggaagc 9660ggtggtcccg gcgcgcgcaa accccacgca cgagaaggtg ctggcgatcg taaacgcgct 9720ggccgaaaac agggccatcc ggcccgacga ggccggcctg gtctacgacg cgctgcttca 9780gcgcgtggct cgttacaaca gcggcaacgt gcagaccaac ctggaccggc tggtggggga 9840tgtgcgcgag gccgtggcgc agcgtgagcg cgcgcagcag cagggcaacc tgggctccat 9900ggttgcacta aacgccttcc tgagtacaca gcccgccaac gtgccgcggg gacaggagga 9960ctacaccaac tttgtgagcg cactgcggct aatggtgact gagacaccgc aaagtgaggt 10020gtaccagtct gggccagact attttttcca gaccagtaga caaggcctgc agaccgtaaa 10080cctgagccag gctttcaaaa acttgcaggg gctgtggggg gtgcgggctc ccacaggcga 10140ccgcgcgacc gtgtctagct tgctgacgcc caactcgcgc ctgttgctgc tgctaatagc 10200gcccttcacg gacagtggca gcgtgtcccg ggacacatac ctaggtcact tgctgacact 10260gtaccgcgag gccataggtc aggcgcatgt ggacgagcat actttccagg agattacaag 10320tgtcagccgc gcgctggggc aggaggacac gggcagcctg gaggcaaccc taaactacct 10380gctgaccaac cggcggcaga agatcccctc gttgcacagt ttaaacagcg aggaggagcg 10440cattttgcgc tacgtgcagc agagcgtgag ccttaacctg atgcgcgacg gggtaacgcc 10500cagcgtggcg ctggacatga ccgcgcgcaa catggaaccg ggcatgtatg cctcaaaccg 10560gccgtttatc aaccgcctaa tggactactt gcatcgcgcg gccgccgtga accccgagta 10620tttcaccaat gccatcttga acccgcactg gctaccgccc cctggtttct acaccggggg 10680attcgaggtg cccgagggta acgatggatt cctctgggac gacatagacg acagcgtgtt 10740ttccccgcaa ccgcagaccc tgctagagtt gcaacagcgc gagcaggcag aggcggcgct 10800gcgaaaggaa agcttccgca ggccaagcag cttgtccgat ctaggcgctg cggccccgcg 10860gtcagatgct agtagcccat ttccaagctt gatagggtct cttaccagca ctcgcaccac 10920ccgcccgcgc ctgctgggcg aggaggagta cctaaacaac tcgctgctgc agccgcagcg 10980cgaaaaaaac ctgcctccgg catttcccaa caacgggata gagagcctag

tggacaagat 11040gagtagatgg aagacgtacg cgcaggagca cagggacgtg ccaggcccgc gcccgcccac 11100ccgtcgtcaa aggcacgacc gtcagcgggg tctggtgtgg gaggacgatg actcggcaga 11160cgacagcagc gtcctggatt tgggagggag tggcaacccg tttgcgcacc ttcgccccag 11220gctggggaga atgttttaaa aaaaaaaaaa gcatgatgca aaataaaaaa ctcaccaagg 11280ccatggcacc gagcgttggt tttcttgtat tccccttagt atgcggcgcg cggcgatgta 11340tgaggaaggt cctcctccct cctacgagag tgtggtgagc gcggcgccag tggcggcggc 11400gctgggttct cccttcgatg ctcccctgga cccgccgttt gtgcctccgc ggtacctgcg 11460gcctaccggg gggagaaaca gcatccgtta ctctgagttg gcacccctat tcgacaccac 11520ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca tccctgaact accagaacga 11580ccacagcaac tttctgacca cggtcattca aaacaatgac tacagcccgg gggaggcaag 11640cacacagacc atcaatcttg acgaccggtc gcactggggc ggcgacctga aaaccatcct 11700gcataccaac atgccaaatg tgaacgagtt catgtttacc aataagttta aggcgcgggt 11760gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag ctgaaatacg agtgggtgga 11820gttcacgctg cccgagggca actactccga gaccatgacc atagacctta tgaacaacgc 11880gatcgtggag cactacttga aagtgggcag acagaacggg gttctggaaa gcgacatcgg 11940ggtaaagttt gacacccgca acttcagact ggggtttgac cccgtcactg gtcttgtcat 12000gcctggggta tatacaaacg aagccttcca tccagacatc attttgctgc caggatgcgg 12060ggtggacttc acccacagcc gcctgagcaa cttgttgggc atccgcaagc ggcaaccctt 12120ccaggagggc tttaggatca cctacgatga tctggagggt ggtaacattc ccgcactgtt 12180ggatgtggac gcctaccagg cgagcttgaa agatgacacc gaacagggcg ggggtggcgc 12240aggcggcagc aacagcagtg gcagcggcgc ggaagagaac tccaacgcgg cagccgcggc 12300aatgcagccg gtggaggaca tgaacgatca tgccattcgc ggcgacacct ttgccacacg 12360ggctgaggag aagcgcgctg aggccgaagc agcggccgaa gctgccgccc ccgctgcgca 12420acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa cccctgacag aggacagcaa 12480gaaacgcagt tacaacctaa taagcaatga cagcaccttc acccagtacc gcagctggta 12540ccttgcatac aactacggcg accctcagac cggaatccgc tcatggaccc tgctttgcac 12600tcctgacgta acctgcggct cggagcaggt ctactggtcg ttgccagaca tgatgcaaga 12660ccccgtgacc ttccgctcca cgcgccagat cagcaacttt ccggtggtgg gcgccgagct 12720gttgcccgtg cactccaaga gcttctacaa cgaccaggcc gtctactccc aactcatccg 12780ccagtttacc tctctgaccc acgtgttcaa tcgctttccc gagaaccaga ttttggcgcg 12840cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt cctgctctca cagatcacgg 12900gacgctaccg ctgcgcaaca gcatcggagg agtccagcga gtgaccatta ctgacgccag 12960acgccgcacc tgcccctacg tttacaaggc cctgggcata gtctcgccgc gcgtcctatc 13020gagccgcact ttttgagcaa gcatgtccat ccttatatcg cccagcaata acacaggctg 13080gggcctgcgc ttcccaagca agatgtttgg cggggccaag aagcgctccg accaacaccc 13140agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg cacaaacgcg gccgcactgg 13200gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag gaggcgcgca actacacgcc 13260cacgccgcca ccagtgtcca cagtggacgc ggccattcag accgtggtgc gcggagcccg 13320gcgctatgct aaaatgaaga gacggcggag gcgcgtagca cgtcgccacc gccgccgacc 13380cggcactgcc gcccaacgcg cggcggcggc cctgcttaac cgcgcacgtc gcaccggccg 13440acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt attgtcactg tgccccccag 13500gtccaggcga cgagcggccg ccgcagcagc cgcggccatt agtgctatga ctcagggtcg 13560caggggcaac gtgtattggg tgcgcgactc ggttagcggc ctgcgcgtgc ccgtgcgcac 13620ccgccccccg cgcaactaga ttgcaagaaa aaactactta gactcgtact gttgtatgta 13680tccagcggcg gcggcgcgca acgaagctat gtccaagcgc aaaatcaaag aagagatgct 13740ccaggtcatc gcgccggaga tctatggccc cccgaagaag gaagagcagg attacaagcc 13800ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat gatgatgaac ttgacgacga 13860ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta cagtggaaag gtcgacgcgt 13920aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg cccggtgagc gctccacccg 13980cacctacaag cgcgtgtatg atgaggtgta cggcgacgag gacctgcttg agcaggccaa 14040cgagcgcctc ggggagtttg cctacggaaa gcggcataag gacatgctgg cgttgccgct 14100ggacgagggc aacccaacac ctagcctaaa gcccgtaaca ctgcagcagg tgctgcccgc 14160gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag tctggtgact tggcacccac 14220cgtgcagctg atggtaccca agcgccagcg actggaagat gtcttggaaa aaatgaccgt 14280ggaacctggg ctggagcccg aggtccgcgt gcggccaatc aagcaggtgg cgccgggact 14340gggcgtgcag accgtggacg ttcagatacc cactaccagt agcaccagta ttgccaccgc 14400cacagagggc atggagacac aaacgtcccc ggttgcctca gcggtggcgg atgccgcggt 14460gcaggcggtc gctgcggccg cgtccaagac ctctacggag gtgcaaacgg acccgtggat 14520gtttcgcgtt tcagcccccc ggcgcccgcg ccgttcgagg aagtacggcg ccgccagcgc 14580gctactgccc gaatatgccc tacatccttc cattgcgcct acccccggct atcgtggcta 14640cacctaccgc cccagaagac gagcaactac ccgacgccga accaccactg gaacccgccg 14700ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc gtgcgcaggg tggctcgcga 14760aggaggcagg accctggtgc tgccaacagc gcgctaccac cccagcatcg tttaaaagcc 14820ggtctttgtg gttcttgcag atatggccct cacctgccgc ctccgtttcc cggtgccggg 14880attccgagga agaatgcacc gtaggagggg catggccggc cacggcctga cgggcggcat 14940gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt cgcatgcgcg gcggtatcct 15000gcccctcctt attccactga tcgccgcggc gattggcgcc gtgcccggaa ttgcatccgt 15060ggccttgcag gcgcagagac actgattaaa aacaagttgc atgtggaaaa atcaaaataa 15120aaagtctgga ctctcacgct cgcttggtcc tgtaactatt ttgtagaatg gaagacatca 15180actttgcgtc tctggccccg cgacacggct cgcgcccgtt catgggaaac tggcaagata 15240tcggcaccag caatatgagc ggtggcgcct tcagctgggg ctcgctgtgg agcggcatta 15300aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc ctggaacagc agcacaggcc 15360agatgctgag ggataagttg aaagagcaaa atttccaaca aaaggtggta gatggcctgg 15420cctctggcat tagcggggtg gtggacctgg ccaaccaggc agtgcaaaat aagattaaca 15480gtaagcttga tccccgccct cccgtagagg agcctccacc ggccgtggag acagtgtctc 15540cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga agaaactctg gtgacgcaaa 15600tagacgagcc tccctcgtac gaggaggcac taaagcaagg cctgcccacc acccgtccca 15660tcgcgcccat ggctaccgga gtgctgggcc agcacacacc cgtaacgctg gacctgcctc 15720cccccgccga cacccagcag aaacctgtgc tgccaggccc gaccgccgtt gttgtaaccc 15780gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc gcgatcgttg cggcccgtag 15840ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg tctgggggtg caatccctga 15900agcgccgacg atgcttctga tagctaacgt gtcgtatgtg tgtcatgtat gcgtccatgt 15960cgccgccaga ggagctgctg agccgccgcg cgcccgcttt ccaagatggc taccccttcg 16020atgatgccgc agtggtctta catgcacatc tcgggccagg acgcctcgga gtacctgagc 16080cccgggctgg tgcagtttgc ccgcgccacc gagacgtact tcagcctgaa taacaagttt 16140agaaacccca cggtggcgcc tacgcacgac gtgaccacag accggtccca gcgtttgacg 16200ctgcggttca tccctgtgga ccgtgaggat actgcgtact cgtacaaggc gcggttcacc 16260ctagctgtgg gtgataaccg tgtgctggac atggcttcca cgtactttga catccgcggc 16320gtgctggaca ggggccctac ttttaagccc tactctggca ctgcctacaa cgccctggct 16380cccaagggtg ccccaaatcc ttgcgaatgg gatgaagctg ctactgctct tgaaataaac 16440ctagaagaag aggacgatga caacgaagac gaagtagacg agcaagctga gcagcaaaaa 16500actcacgtat ttgggcaggc gccttattct ggtataaata ttacaaagga gggtattcaa 16560ataggtgtcg aaggtcaaac acctaaatat gccgataaaa catttcaacc tgaacctcaa 16620ataggagaat ctcagtggta cgaaacagaa attaatcatg cagctgggag agtcctaaaa 16680aagactaccc caatgaaacc atgttacggt tcatatgcaa aacccacaaa tgaaaatgga 16740gggcaaggca ttcttgtaaa gcaacaaaat ggaaagctag aaagtcaagt ggaaatgcaa 16800tttttctcaa ctactgaggc agccgcaggc aatggtgata acttgactcc taaagtggta 16860ttgtacagtg aagatgtaga tatagaaacc ccagacactc atatttctta catgcccact 16920attaaggaag gtaactcacg agaactaatg ggccaacaat ctatgcccaa caggcctaat 16980tacattgctt ttagggacaa ttttattggt ctaatgtatt acaacagcac gggtaatatg 17040ggtgttctgg cgggccaagc atcgcagttg aatgctgttg tagatttgca agacagaaac 17100acagagcttt cataccagct tttgcttgat tccattggtg atagaaccag gtacttttct 17160atgtggaatc aggctgttga cagctatgat ccagatgtta gaattattga aaatcatgga 17220actgaagatg aacttccaaa ttactgcttt ccactgggag gtgtgattaa tacagagact 17280cttaccaagg taaaacctaa aacaggtcag gaaaatggat gggaaaaaga tgctacagaa 17340ttttcagata aaaatgaaat aagagttgga aataattttg ccatggaaat caatctaaat 17400gccaacctgt ggagaaattt cctgtactcc aacatagcgc tgtatttgcc cgacaagcta 17460aagtacagtc cttccaacgt aaaaatttct gataacccaa acacctacga ctacatgaac 17520aagcgagtgg tggctcccgg gctagtggac tgctacatta accttggagc acgctggtcc 17580cttgactata tggacaacgt caacccattt aaccaccacc gcaatgctgg cctgcgctac 17640cgctcaatgt tgctgggcaa tggtcgctat gtgcccttcc acatccaggt gcctcagaag 17700ttctttgcca ttaaaaacct ccttctcctg ccgggctcat acacctacga gtggaacttc 17760aggaaggatg ttaacatggt tctgcagagc tccctaggaa atgacctaag ggttgacgga 17820gccagcatta agtttgatag catttgcctt tacgccacct tcttccccat ggcccacaac 17880accgcctcca cgcttgaggc catgcttaga aacgacacca acgaccagtc ctttaacgac 17940tatctctccg ccgccaacat gctctaccct atacccgcca acgctaccaa cgtgcccata 18000tccatcccct cccgcaactg ggcggctttc cgcggctggg ccttcacgcg ccttaagact 18060aaggaaaccc catcactggg ctcgggctac gacccttatt acacctactc tggctctata 18120ccctacctag atggaacctt ttacctcaac cacaccttta agaaggtggc cattaccttt 18180gactcttctg tcagctggcc tggcaatgac cgcctgctta cccccaacga gtttgaaatt 18240aagcgctcag ttgacgggga gggttacaac gttgcccagt gtaacatgac caaagactgg 18300ttcctggtac aaatgctagc taactataac attggctacc agggcttcta tatcccagag 18360agctacaagg accgcatgta ctccttcttt agaaacttcc agcccatgag ccgtcaggtg 18420gtggatgata ctaaatacaa ggactaccaa caggtgggca tcctacacca acacaacaac 18480tctggatttg ttggctacct tgcccccacc atgcgcgaag gacaggccta ccctgctaac 18540ttcccctatc cgcttatagg caagaccgca gttgacagca ttacccagaa aaagtttctt 18600tgcgatcgca ccctttggcg catcccattc tccagtaact ttatgtccat gggcgcactc 18660acagacctgg gccaaaacct tctctacgcc aactccgccc acgcgctaga catgactttt 18720gaggtggatc ccatggacga gcccaccctt ctttatgttt tgtttgaagt ctttgacgtg 18780gtccgtgtgc accagccgca ccgcggcgtc atcgaaaccg tgtacctgcg cacgcccttc 18840tcggccggca acgccacaac ataaagaagc aagcaacatc aacaacagct gccgccatgg 18900gctccagtga gcaggaactg aaagccattg tcaaagatct tggttgtggg ccatattttt 18960tgggcaccta tgacaagcgc tttccaggct ttgtttctcc acacaagctc gcctgcgcca 19020tagtcaatac ggccggtcgc gagactgggg gcgtacactg gatggccttt gcctggaacc 19080cgcactcaaa aacatgctac ctctttgagc cctttggctt ttctgaccag cgactcaagc 19140aggtttacca gtttgagtac gagtcactcc tgcgccgtag cgccattgct tcttcccccg 19200accgctgtat aacgctggaa aagtccaccc aaagcgtaca ggggcccaac tcggccgcct 19260gtggactatt ctgctgcatg tttctccacg cctttgccaa ctggccccaa actcccatgg 19320atcacaaccc caccatgaac cttattaccg gggtacccaa ctccatgctc aacagtcccc 19380aggtacagcc caccctgcgt cgcaaccagg aacagctcta cagcttcctg gagcgccact 19440cgccctactt ccgcagccac agtgcgcaga ttaggagcgc cacttctttt tgtcacttga 19500aaaacatgta aaaataatgt actagagaca ctttcaataa aggcaaatgc ttttatttgt 19560acactctcgg gtgattattt acccccaccc ttgccgtctg cgccgtttaa aaatcaaagg 19620ggttctgccg cgcatcgcta tgcgccactg gcagggacac gttgcgatac tggtgtttag 19680tgctccactt aaactcaggc acaaccatcc gcggcagctc ggtgaagttt tcactccaca 19740ggctgcgcac catcaccaac gcgtttagca ggtcgggcgc cgatatcttg aagtcgcagt 19800tggggcctcc gccctgcgcg cgcgagttgc gatacacagg gttgcagcac tggaacacta 19860tcagcgccgg gtggtgcacg ctggccagca cgctcttgtc ggagatcaga tccgcgtcca 19920ggtcctccgc gttgctcagg gcgaacggag tcaactttgg tagctgcctt cccaaaaagg 19980gcgcgtgccc aggctttgag ttgcactcgc accgtagtgg catcaaaagg tgaccgtgcc 20040cggtctgggc gttaggatac agcgcctgca taaaagcctt gatctgctta aaagccacct 20100gagcctttgc gccttcagag aagaacatgc cgcaagactt gccggaaaac tgattggccg 20160gacaggccgc gtcgtgcacg cagcaccttg cgtcggtgtt ggagatctgc accacatttc 20220ggccccaccg gttcttcacg atcttggcct tgctagactg ctccttcagc gcgcgctgcc 20280cgttttcgct cgtcacatcc atttcaatca cgtgctcctt atttatcata atgcttccgt 20340gtagacactt aagctcgcct tcgatctcag cgcagcggtg cagccacaac gcgcagcccg 20400tgggctcgtg atgcttgtag gtcacctctg caaacgactg caggtacgcc tgcaggaatc 20460gccccatcat cgtcacaaag gtcttgttgc tggtgaaggt cagctgcaac ccgcggtgct 20520cctcgttcag ccaggtcttg catacggccg ccagagcttc cacttggtca ggcagtagtt 20580tgaagttcgc ctttagatcg ttatccacgt ggtacttgtc catcagcgcg cgcgcagcct 20640ccatgccctt ctcccacgca gacacgatcg gcacactcag cgggttcatc accgtaattt 20700cactttccgc ttcgctgggc tcttcctctt cctcttgcgt ccgcatacca cgcgccactg 20760ggtcgtcttc attcagccgc cgcactgtgc gcttacctcc tttgccatgc ttgattagca 20820ccggtgggtt gctgaaaccc accatttgta gcgccacatc ttctctttct tcctcgctgt 20880ccacgattac ctctggtgat ggcgggcgct cgggcttggg agaagggcgc ttctttttct 20940tcttgggcgc aatggccaaa tccgccgccg aggtcgatgg ccgcgggctg ggtgtgcgcg 21000gcaccagcgc gtcttgtgat gagtcttcct cgtcctcgga ctcgatacgc cgcctcatcc 21060gcttttttgg gggcgcccgg ggaggcggcg gcgacgggga cggggacgac acgtcctcca 21120tggttggggg acgtcgcgcc gcaccgcgtc cgcgctcggg ggtggtttcg cgctgctcct 21180cttcccgact ggccatttcc ttctcctata ggcagaaaaa gatcatggag tcagtcgaga 21240agaaggacag cctaaccgcc ccctctgagt tcgccaccac cgcctccacc gatgccgcca 21300acgcgcctac caccttcccc gtcgaggcac ccccgcttga ggaggaggaa gtgattatcg 21360agcaggaccc aggttttgta agcgaagacg acgaggaccg ctcagtacca acagaggata 21420aaaagcaaga ccaggacaac gcagaggcaa acgaggaaca agtcgggcgg ggggacgaaa 21480ggcatggcga ctacctagat gtgggagacg acgtgctgtt gaagcatctg cagcgccagt 21540gcgccattat ctgcgacgcg ttgcaagagc gcagcgatgt gcccctcgcc atagcggatg 21600tcagccttgc ctacgaacgc cacctattct caccgcgcgt accccccaaa cgccaagaaa 21660acggcacatg cgagcccaac ccgcgcctca acttctaccc cgtatttgcc gtgccagagg 21720tgcttgccac ctatcacatc tttttccaaa actgcaagat acccctatcc tgccgtgcca 21780accgcagccg agcggacaag cagctggcct tgcggcaggg cgctgtcata cctgatatcg 21840cctcgctcaa cgaagtgcca aaaatctttg agggtcttgg acgcgacgag aagcgcgcgg 21900caaacgctct gcaacaggaa aacagcgaaa atgaaagtca ctctggagtg ttggtggaac 21960tcgagggtga caacgcgcgc ctagccgtac taaaacgcag catcgaggtc acccactttg 22020cctacccggc acttaaccta ccccccaagg tcatgagcac agtcatgagt gagctgatcg 22080tgcgccgtgc gcagcccctg gagagggatg caaatttgca agaacaaaca gaggagggcc 22140tacccgcagt tggcgacgag cagctagcgc gctggcttca aacgcgcgag cctgccgact 22200tggaggagcg acgcaaacta atgatggccg cagtgctcgt taccgtggag cttgagtgca 22260tgcagcggtt ctttgctgac ccggagatgc agcgcaagct agaggaaaca ttgcactaca 22320cctttcgaca gggctacgta cgccaggcct gcaagatctc caacgtggag ctctgcaacc 22380tggtctccta ccttggaatt ttgcacgaaa accgccttgg gcaaaacgtg cttcattcca 22440cgctcaaggg cgaggcgcgc cgcgactacg tccgcgactg cgtttactta tttctatgct 22500acacctggca gacggccatg ggcgtttggc agcagtgctt ggaggagtgc aacctcaagg 22560agctgcagaa actgctaaag caaaacttga aggacctatg gacggccttc aacgagcgct 22620ccgtggccgc gcacctggcg gacatcattt tccccgaacg cctgcttaaa accctgcaac 22680agggtctgcc agacttcacc agtcaaagca tgttgcagaa ctttaggaac tttatcctag 22740agcgctcagg aatcttgccc gccacctgct gtgcacttcc tagcgacttt gtgcccatta 22800agtaccgcga atgccctccg ccgctttggg gccactgcta ccttctgcag ctagccaact 22860accttgccta ccactctgac ataatggaag acgtgagcgg tgacggtcta ctggagtgtc 22920actgtcgctg caacctatgc accccgcacc gctccctggt ttgcaattcg cagctgctta 22980acgaaagtca aattatcggt acctttgagc tgcagggtcc ctcgcctgac gaaaagtccg 23040cggctccggg gttgaaactc actccggggc tgtggacgtc ggcttacctt cgcaaatttg 23100tacctgagga ctaccacgcc cacgagatta ggttctacga agaccaatcc cgcccgccta 23160atgcggagct taccgcctgc gtcattaccc agggccacat tcttggccaa ttgcaagcca 23220tcaacaaagc ccgccaagag tttctgctac gaaagggacg gggggtttac ttggaccccc 23280agtccggcga ggagctcaac ccaatccccc cgccgccgca gccctatcag cagcagccgc 23340gggcccttgc ttcccaggat ggcacccaaa aagaagctgc agctgccgcc gccacccacg 23400gacgaggagg aatactggga cagtcaggca gaggaggttt tggacgagga ggaggaggac 23460atgatggaag actgggagag cctagacgag gaagcttccg aggtcgaaga ggtgtcagac 23520gaaacaccgt caccctcggt cgcattcccc tcgccggcgc cccagaaatc ggcaaccggt 23580tccagcatgg ctacaacctc cgctcctcag gcgccgccgg cactgcccgt tcgccgaccc 23640aaccgtagat gggacaccac tggaaccagg gccggtaagt ccaagcagcc gccgccgtta 23700gcccaagagc aacaacagcg ccaaggctac cgctcatggc gcgggcacaa gaacgccata 23760gttgcttgct tgcaagactg tgggggcaac atctccttcg cccgccgctt tcttctctac 23820catcacggcg tggccttccc ccgtaacatc ctgcattact accgtcatct ctacagccca 23880tactgcaccg gcggcagcgg cagcaacagc agcggccaca cagaagcaaa ggcgaccgga 23940tagcaagact ctgacaaagc ccaagaaatc cacagcggcg gcagcagcag gaggaggagc 24000gctgcgtctg gcgcccaacg aacccgtatc gacccgcgag cttagaaaca ggatttttcc 24060cactctgtat gctatatttc aacagagcag gggccaagaa caagagctga aaataaaaaa 24120caggtctctg cgatccctca cccgcagctg cctgtatcac aaaagcgaag atcagcttcg 24180gcgcacgctg gaagacgcgg aggctctctt cagtaaatac tgcgcgctga ctcttaagga 24240ctagtttcgc gccctttctc aaatttaagc gcgaaaacta cgtcatctcc agcggccaca 24300cccggcgcca gcacctgttg tcagcgccat tatgagcaag gaaattccca cgccctacat 24360gtggagttac cagccacaaa tgggacttgc ggctggagct gcccaagact actcaacccg 24420aataaactac atgagcgcgg gaccccacat gatatcccgg gtcaacggaa tacgcgccca 24480ccgaaaccga attctcctgg aacaggcggc tattaccacc acacctcgta ataaccttaa 24540tccccgtagt tggcccgctg ccctggtgta ccaggaaagt cccgctccca ccactgtggt 24600acttcccaga gacgcccagg ccgaagttca gatgactaac tcaggggcgc agcttgcggg 24660cggctttcgt cacagggtgc ggtcgcccgg gcagggtata actcacctga caatcagagg 24720gcgaggtatt cagctcaacg acgagtcggt gagctcctcg cttggtctcc gtccggacgg 24780gacatttcag atcggcggcg ccggccgctc ttcattcacg cctcgtcagg caatcctaac 24840tctgcagacc tcgtcctctg agccgcgctc tggaggcatt ggaactctgc aatttattga 24900ggagtttgtg ccatcggtct actttaaccc cttctcggga cctcccggcc actatccgga 24960tcaatttatt cctaactttg acgcggtaaa ggactcggcg gacggctacg actgaatgtt 25020aagtggagag gcagagcaac tgcgcctgaa acacctggtc cactgtcgcc gccacaagtg 25080ctttgcccgc gactccggtg agttttgcta ctttgaattg cccgaggatc atatcgaggg 25140cccggcgcac ggcgtccggc ttaccgccca gggagagctt gcccgtagcc tgattcggga 25200gtttacccag cgccccctgc tagttgagcg ggacagggga ccctgtgttc tcactgtgat 25260ttgcaactgt cctaaccctg gattacatca agatctttgt tgccatctct gtgctgagta 25320taataaatac agaaattaaa atatactggg gctcctatcg ccatcctgta aacgccaccg 25380tcttcacccg cccaagcaaa ccaaggcgaa ccttacctgg tacttttaac atctctccct 25440ctgtgattta caacagtttc aacccagacg gagtgagtct acgagagaac ctctccgagc 25500tcagctactc catcagaaaa aacaccaccc tccttacctg ccgggaacgt acgagtgcgt 25560caccggccgc tgcaccacac ctaccgcctg accgtaaacc agactttttc cggacagacc 25620tcaataactc tgtttaccag aacaggaggt gagcttagaa aacccttagg gtattaggcc 25680aaaggcgcag ctactgtggg gtttatgaac aattcaagca actctacggg ctattctaat 25740tcaggtttct ctagaatcgg ggttggggtt attctctgtc ttgtgattct ctttattctt 25800atactaacgc ttctctgcct aaggctcgcc gcctgctgtg tgcacatttg catttattgt 25860cagcttttta aacgctgggg tcgccaccca agatgattag gtacataatc ctaggtttac 25920tcacccttgc gtcagcccac ggtaccaccc aaaaggtgga ttttaaggag ccagcctgta 25980atgttacatt cgcagctgaa gctaatgagt gcaccactct tataaaatgc accacagaac 26040atgaaaagct gcttattcgc cacaaaaaca aaattggcaa gtatgctgtt

tatgctattt 26100ggcagccagg tgacactaca gagtataatg ttacagtttt ccagggtaaa agtcataaaa 26160cttttatgta tacttttcca ttttatgaaa tgtgcgacat taccatgtac atgagcaaac 26220agtataagtt gtggccccca caaaattgtg tggaaaacac tggcactttc tgctgcactg 26280ctatgctaat tacagtgctc gctttggtct gtaccctact ctatattaaa tacaaaagca 26340gacgcagctt tattgaggaa aagaaaatgc cttaatttac taagttacaa agctaatgtc 26400accactaact gctttactcg ctgcttgcaa aacaaattca aaaagttagc attataatta 26460gaataggatt taaacccccc ggtcatttcc tgctcaatac cattcccctg aacaattgac 26520tctatgtggg atatgctcca gcgctacaac cttgaagtca ggcttcctgg atgtcagcat 26580ctgactttgg ccagcacctg tcccgcggat ttgttccagt ccaactacag cgacccaccc 26640taacagagat gaccaacaca accaacgcgg ccgccgctac cggacttaca tctaccacaa 26700atacacccca agtttctgcc tttgtcaata actgggataa cttgggcatg tggtggttct 26760ccatagcgct tatgtttgta tgccttatta ttatgtggct catctgctgc ctaaagcgca 26820aacgcgcccg accacccatc tatagtccca tcattgtgct acacccaaac aatgatggaa 26880tccatagatt ggacggactg aaacacatgt tcttttctct tacagtatga ttaaatgaga 26940catgattcct cgagttttta tattactgac ccttgttgcg ctttttttgt gcgtgctcca 27000cattggctgc ggtttctcac atcgaagtag actgcattcc agccttcaca gtctatttgc 27060tttacggatt tgtcaccctc acgctcatct gcagcctcat cactgtggtc atcgccttta 27120tccagtgcat tgactgggtc tgtgtgcgct ttgcatatct cagacaccat ccccagtaca 27180gggacaggac tatagctgag cttcttagaa ttctttaatt atgaaattta ctgtgacttt 27240tctgctgatt atttgcaccc tatctgcgtt ttgttccccg acctccaagc ctcaaagaca 27300tatatcatgc agattcactc gtatatggaa tattccaagt tgctacaatg aaaaaagcga 27360tctttccgaa gcctggttat atgcaatcat ctctgttatg gtgttctgca gtaccatctt 27420agccctagct atatatccct accttgacat tggctggaac gcaatagatg ccatgaacca 27480cccaactttc cccgcgcccg ctatgcttcc actgcaacaa gttgttgccg gcggctttgt 27540cccagccaat cagcctcgcc caccttctcc cacccccact gaaatcagct actttaatct 27600aacaggagga gatgactgac accctagatc tagaaatgga cggaattatt acagagcagc 27660gcctgctaga aagacgcagg gcagcggccg agcaacagcg catgaatcaa gagctccaag 27720acatggttaa cttgcaccag tgcaaaaggg gtatcttttg tctggtaaag caggccaaag 27780tcacctacga cagtaatacc accggacacc gccttagcta caagttgcca accaagcgtc 27840agaaattggt ggtcatggtg ggagaaaagc ccattaccat aactcagcac tcggtagaaa 27900ccgaaggctg cattcactca ccttgtcaag gacctgagga tctctgcacc cttattaaga 27960ccctgtgcgg tctcaaagat cttattccct ttaactaata aaaaaaaata ataaagcatc 28020acttacttaa aatcagttag caaatttctg tccagtttat tcagcagcac ctccttgccc 28080tcctcccagc tctggtattg cagcttcctc ctggctgcaa actttctcca caatctaaat 28140ggaatgtcag tttcctcctg ttcctgtcca tccgcaccca ctatcttcat gttgttgcag 28200atgaagcgcg caagaccgtc tgaagatacc ttcaaccccg tgtatccata tgacacggaa 28260accggtcctc caactgtgcc ttttcttact cctccctttg tatcccccaa tgggtttcaa 28320gagagtcccc ctggggtact ctctttgcgc ctatccgaac ctctagttac ctccaatggc 28380atgcttgcgc tcaaaatggg caacggcctc tctctggacg aggccggcaa ccttacctcc 28440caaaatgtaa ccactgtgag cccacctctc aaaaaaacca agtcaaacat aaacctggaa 28500atatctgcac ccctcacagt tacctcagaa gccctaactg tggctgccgc cgcacctcta 28560atggtcgcgg gcaacacact caccatgcaa tcacaggccc cgctaaccgt gcacgactcc 28620aaacttagca ttgccaccca aggacccctc acagtgtcag aaggaaagct agccctgcaa 28680acatcaggcc ccctcaccac caccgatagc agtaccctta ctatcactgc ctcaccccct 28740ctaactactg ccactggtag cttgggcatt gacttgaaag agcccattta tacacaaaat 28800ggaaaactag gactaaagta cggggctcct ttgcatgtaa cagacgacct aaacactttg 28860accgtagcaa ctggtccagg tgtgactatt aataatactt ccttgcaaac taaagttact 28920ggagccttgg gttttgattc acaaggcaat atgcaactta atgtagcagg aggactaagg 28980attgattctc aaaacagacg ccttatactt gatgttagtt atccgtttga tgctcaaaac 29040caactaaatc taagactagg acagggccct ctttttataa actcagccca caacttggat 29100attaactaca acaaaggcct ttacttgttt acagcttcaa acaattccaa aaagcttgag 29160gttaacctaa gcactgccaa ggggttgatg tttgacgcta cagccatagc cattaatgca 29220ggagatgggc ttgaatttgg ttcacctaat gcaccaaaca caaatcccct caaaacaaaa 29280attggccatg gcctagaatt tgattcaaac aaggctatgg ttcctaaact aggaactggc 29340cttagttttg acagcacagg tgccattaca gtaggaaaca aaaataatga taagctaact 29400ttgtggacca caccagctcc atctcctaac tgtagactaa atgcagagaa agatgctaaa 29460ctcactttgg tcttaacaaa atgtggcagt caaatacttg ctacagtttc agttttggct 29520gttaaaggca gtttggctcc aatatctgga acagttcaaa gtgctcatct tattataaga 29580tttgacgaaa atggagtgct actaaacaat tccttcctgg acccagaata ttggaacttt 29640agaaatggag atcttactga aggcacagcc tatacaaacg ctgttggatt tatgcctaac 29700ctatcagctt atccaaaatc tcacggtaaa actgccaaaa gtaacattgt cagtcaagtt 29760tacttaaacg gagacaaaac taaacctgta acactaacca ttacactaaa cggtacacag 29820gaaacaggag acacaactcc aagtgcatac tctatgtcat tttcatggga ctggtctggc 29880cacaactaca ttaatgaaat atttgccaca tcctcttaca ctttttcata cattgcccaa 29940gaataaagaa tcgtttgtgt tatgtttcaa cgtgtttatt tttcaattgc agaaaatttc 30000aagtcatttt tcattcagta gtatagcccc accaccacat agcttataca gatcaccgta 30060ccttaatcaa actcacagaa ccctagtatt caacctgcca cctccctccc aacacacaga 30120gtacacagtc ctttctcccc ggctggcctt aaaaagcatc atatcatggg taacagacat 30180attcttaggt gttatattcc acacggtttc ctgtcgagcc aaacgctcat cagtgatatt 30240aataaactcc ccgggcagct cacttaagtt catgtcgctg tccagctgct gagccacagg 30300ctgctgtcca acttgcggtt gcttaacggg cggcgaagga gaagtccacg cctacatggg 30360ggtagagtca taatcgtgca tcaggatagg gcggtggtgc tgcagcagcg cgcgaataaa 30420ctgctgccgc cgccgctccg tcctgcagga atacaacatg gcagtggtct cctcagcgat 30480gattcgcacc gcccgcagca taaggcgcct tgtcctccgg gcacagcagc gcaccctgat 30540ctcacttaaa tcagcacagt aactgcagca cagcaccaca atattgttca aaatcccaca 30600gtgcaaggcg ctgtatccaa agctcatggc ggggaccaca gaacccacgt ggccatcata 30660ccacaagcgc aggtagatta agtggcgacc cctcataaac acgctggaca taaacattac 30720ctcttttggc atgttgtaat tcaccacctc ccggtaccat ataaacctct gattaaacat 30780ggcgccatcc accaccatcc taaaccagct ggccaaaacc tgcccgccgg ctatacactg 30840cagggaaccg ggactggaac aatgacagtg gagagcccag gactcgtaac catggatcat 30900catgctcgtc atgatatcaa tgttggcaca acacaggcac acgtgcatac acttcctcag 30960gattacaagc tcctcccgcg ttagaaccat atcccaggga acaacccatt cctgaatcag 31020cgtaaatccc acactgcagg gaagacctcg cacgtaactc acgttgtgca ttgtcaaagt 31080gttacattcg ggcagcagcg gatgatcctc cagtatggta gcgcgggttt ctgtctcaaa 31140aggaggtaga cgatccctac tgtacggagt gcgccgagac aaccgagatc gtgttggtcg 31200tagtgtcatg ccaaatggaa cgccggacgt agtcatattt cctgaagcaa aaccaggtgc 31260gggcgtgaca aacagatctg cgtctccggt ctcgccgctt agatcgctct gtgtagtagt 31320tgtagtatat ccactctctc aaagcatcca ggcgccccct ggcttcgggt tctatgtaaa 31380ctccttcatg cgccgctgcc ctgataacat ccaccaccgc agaataagcc acacccagcc 31440aacctacaca ttcgttctgc gagtcacaca cgggaggagc gggaagagct ggaagaacca 31500tgtttttttt tttattccaa aagattatcc aaaacctcaa aatgaagatc tattaagtga 31560acgcgctccc ctccggtggc gtggtcaaac tctacagcca aagaacagat aatggcattt 31620gtaagatgtt gcacaatggc ttccaaaagg caaacggccc tcacgtccaa gtggacgtaa 31680aggctaaacc cttcagggtg aatctcctct ataaacattc cagcaccttc aaccatgccc 31740aaataattct catctcgcca ccttctcaat atatctctaa gcaaatcccg aatattaagt 31800ccggccattg taaaaatctg ctccagagcg ccctccacct tcagcctcaa gcagcgaatc 31860atgattgcaa aaattcaggt tcctcacaga cctgtataag attcaaaagc ggaacattaa 31920caaaaatacc gcgatcccgt aggtcccttc gcagggccag ctgaacataa tcgtgcaggt 31980ctgcacggac cagcgcggcc acttccccgc caggaaccat gacaaaagaa cccacactga 32040ttatgacacg catactcgga gctatgctaa ccagcgtagc cccgatgtaa gcttgttgca 32100tgggcggcga tataaaatgc aaggtgctgc tcaaaaaatc aggcaaagcc tcgcgcaaaa 32160aagaaagcac atcgtagtca tgctcatgca gataaaggca ggtaagctcc ggaaccacca 32220cagaaaaaga caccattttt ctctcaaaca tgtctgcggg tttctgcata aacacaaaat 32280aaaataacaa aaaaacattt aaacattaga agcctgtctt acaacaggaa aaacaaccct 32340tataagcata agacggacta cggccatgcc ggcgtgaccg taaaaaaact ggtcaccgtg 32400attaaaaagc accaccgaca gctcctcggt catgtccgga gtcataatgt aagactcggt 32460aaacacatca ggttgattca catcggtcag tgctaaaaag cgaccgaaat agcccggggg 32520aatacatacc cgcaggcgta gagacaacat tacagccccc ataggaggta taacaaaatt 32580aataggagag aaaaacacat aaacacctga aaaaccctcc tgcctaggca aaatagcacc 32640ctcccgctcc agaacaacat acagcgcttc cacagcggca gccataacag tcagccttac 32700cagtaaaaaa gaaaacctat taaaaaaaca ccactcgaca cggcaccagc tcaatcagtc 32760acagtgtaaa aaagggccaa gtgcagagcg agtatatata ggactaaaaa atgacgtaac 32820ggttaaagtc cacaaaaaac acccagaaaa ccgcacgcga acctacgccc agaaacgaaa 32880gccaaaaaac ccacaacttc ctcaaatcgt cacttccgtt ttcccacgtt acgtcacttc 32940ccattttaag aaaactacaa ttcccaacac atacaagtta ctccgcccta aaacctacgt 33000cacccgcccc gttcccacgc cccgcgccac gtcacaaact ccaccccctc attatcatat 33060tggcttcaat ccaaaataag gtatattatt gat 3309312978DNAArtificial sequencePPE-1-3X promoter 12acgtgtactt ctgatcggcg atactaggga gataaggatg tacctgacaa aaccacattg 60ttgttgttat cattattatt tagttttcct tccttgctaa ctcctgacgg aatctttctc 120acctcaaatg cgaagtactt tagtttagaa aagacttggt ggaaggggtg gtggtggaaa 180agtagggtga tcttccaaac taatctggtt ccccgcccgc cccagtagct gggattcaag 240agcgaagagt ggggatcgtc cccttgtttg atcagaaaga cataaaagga aaatcaagtg 300aacaatgatc agccccacct ccaccccacc cccctgcgcg cgcacaatac aatctattta 360attgtacttc atacttttca ttccaatggg gtgactttgc ttctggagaa actcttgatt 420cttgaactct ggggctggca gctagcctcc agaagcaaag tcaccccatt ggaatgaaaa 480gtatgaagta caatgaaaag tatgaagtac tggctccaga agcaaagtca ccctccagaa 540gcaaagtcac cccattggaa tgaaaagtat gaagtacgct agcaaaaggg gaagcgggct 600gctgctctct gcaggttctg cagcggtctc tgtctagtgg gtgttttctt tttcttagcc 660ctgcccctgg attgtcagac ggcgggcgtc tgcctctgaa gttagccgtg atttcctcta 720gagccgggtc ttatctctgg ctgcacgttg cctgtgggtg actaatcaca caataacatt 780gtttagggct ggaataaagt cagagctgtt tacccccact ctataggggt tcaatataaa 840aaggcggcgg agaactgtcc gagtcagaag cgttcctgca ccggcgctga gagcctgacc 900cggtctgctc cgctgtcctt gcgcgctgcc tcccggctgc ccgcgacgct ttcgccccag 960tggaagggcc acttgctg 978131334DNAMus musculus 13gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtagtgta cttctgatcg 60gcgatactag ggagataagg atgtacctga caaaaccaca ttgttgttgt tatcattatt 120atttagtttt ccttccttgc taactcctga cggaatcttt ctcacctcaa atgcgaagta 180ctttagttta gaaaagactt ggtggaaggg gtggtggtgg aaaagtaggg tgatcttcca 240aactaatctg gttccccgcc cgccccagta gctgggattc aagagcgaag agtggggatc 300gtccccttgt ttgatcagaa agacataaaa ggaaaatcaa gtgaacaatg atcagcccca 360cctccacccc acccccctgc gcgcgcacaa tacaatctat ttaattgtac ttcatacttt 420tcattccaat ggggtgactt tgcttctgga gaaactcttg attcttgaac tctggggctg 480gcagctagca aaaggggaag cgggctgctg ctctctgcag gttctgcagc ggtctctgtc 540tagtgggtgt tttctttttc ttagccctgc ccctggattg tcagacggcg ggcgtctgcc 600tctgaagtta gccgtgattt cctctagagc cgggtcttat ctctggctgc acgttgcctg 660tgggtgacta atcacacaat aacattgttt agggctggaa taaagtcaga gctgtttacc 720cccactctat aggggttcaa tataaaaagg cggcggagaa ctgtccgagt cagacgcgtt 780cctgcaccgg cgctgagagc ctgacccggt ctgctccgct gtccttgcgc gctgcctccc 840ggctgcccgc gacgctttcg ccccagtgga agggccactt gctgaggacc gcgctgagat 900ctaaaaaaaa aacaaaaaac aaaaaacaaa aaaacccaga ggcgatcaga gcgaccagac 960accgtcctct tcgttttgca ttgagttcca tttgcaaccg agttttcttt ttttcctttt 1020tccccactct tctgacccct ttgcagaatg gattattttc ccgtgatctt ctctctgctg 1080ttcgtgactt tccaaggagc tccagaaaca ggtaggcgcc acttgcgaat ctttctactt 1140cagcgcagca gttatcgctt ctgttttcca cttttctttc tttcttttct ttcattcttt 1200cctttttatt tattttttta attactgaag ctccagcagc aagtgcctta caattaatta 1260acttctgtgt gaagcgaaag aaataaaacc cctgtttgaa tacagctgac tacaaccgag 1320tatcgcatag cttc 1334

Claims

1. (canceled)

2. (canceled)

3. A method of treating a malignant glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a viral vector comprising: (i) a first polynucleotide sequence encoding a Fas-chimera (Fas c); and (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter, thereby treating the malignant glioma.

4. The method of claim 3, wherein said promoter is the sequence set forth in SEQ ID NO: 12.

5. The method of claim 3, wherein said promoter is the sequence set forth in SEQ ID NO: 13.

6. The method of claim 3, wherein the viral vector is an adenoviral vector.

7. The method of claim 6, wherein said adenoviral vector is a non-replicating adenoviral vector.

8. The method of claim 3, wherein said promoter comprises at least one copy of the sequence set forth in SEQ ID NO: 6, or the complementary sequence thereof.

9. The method of claim 8, wherein said promoter comprises at least two copies of the sequence set forth in SEQ ID NO: 6, or the complementary sequence thereof.

10. The method of claim 8, wherein said promoter comprises the sequence set forth in SEQ ID NO: 8, or the complementary sequence thereof.

11. The method of claim 8, wherein said promoter comprises the sequence set forth in SEQ ID NO: 7, or the complementary sequence thereof.

12. The method of claim 3, wherein said promoter comprises the hypoxia response element (HRE) set forth in SEQ ID NO: 5.

13. The method of claim 3, wherein the viral vector consists of the sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10.

14. The method of claim 3, wherein the malignant glioma is selected from the group consisting of glioblastoma, astrocytoma, oligodendroglioma, ependymoma, and juvenile pilocystic astrocytoma.

15. The method of claim 3, wherein the therapeutically effective amount of said viral vector is about 10.sup.3 to about 10.sup.16 virus particles.

16. The method of claim 15, wherein the therapeutically effective amount of said viral vector is about 10.sup.5 to about 10.sup.13 virus particles.

17. The method of claim 15, wherein the therapeutically effective amount of said viral vector is about 10.sup.7 to about 10.sup.12 virus particles.

18. The method of claim 15, wherein the therapeutically effective amount of said viral vector is about 1_×.sub.--10.sup.12 to about 5.times..sub.--10.sup.12 virus particles.

19. The method of claim 15, wherein the therapeutically effective amount of said viral vector is about 1_×.sub.--10.sup.13 to about 5.times..sub.--10.sup.13 virus particles.

20. The method of claim 3, wherein said administering comprises intravenous administration.

21. The method of claim 3, wherein said administering comprises local administration.

22. The method of claim 3, wherein said administering is in at least two doses of said viral vector.

23. The method of claim 3, wherein said administering is in at least three doses of said viral vector.

24. The method of claim 3, wherein the viral vector is administered as a single unit dose.

25. The method of claim 3, wherein the Fas-c comprises an extracellular domain of TNFR1 and a trans-membrane region and an intracellular region of Fas polypeptide.

26. The method of claim 25, wherein the Fas-c comprises SEQ ID NO: 2 and SEQ ID NO: 3.

27. The method of claim 3, further comprising administering to the subject an anti-cancer drug.

28. The method of claim 27, wherein said anti-cancer drug is bevacizumab.

29. The method of claim 3, further comprising administering a therapy selected from the group consisting of chemotherapy, radiotherapy, phototherapy and photodynamic therapy, surgery, nutritional therapy, ablative therapy, brachiotherapy, proton beam therapy, immunotherapy, cellular therapy and photon beam radiosurgical therapy.

30. The method of claim 28, wherein said therapy is immunotherapy.