Patent Publication Number: US-2003232770-A1

Title: Antisense modulation of hypothetical tumor endothelial marker expression

Description:
FIELD OF THE INVENTION  
       [0001] The present invention provides compositions and methods for modulating the expression of hypothetical tumor endothelial marker. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding hypothetical tumor endothelial marker. Such compounds have been shown to modulate the expression of hypothetical tumor endothelial marker.  
       BACKGROUND OF THE INVENTION  
       [0002] Tumors require a blood supply for expansive growth, making inhibition of tumor angiogenesis a very useful anticancer strategy. There are several advantages of targeting the endothelial cell which line tumor vessels rather than the tumor cells themselves. Targeting endothelial cells rather than tumor cells obviates many of the pharmacokinetic problems associated with drug delivery. In addition, a significant bystander effect can also be expected because each endothelial cell supports the growth of many tumor cells and targeting the genetically stable endothelial cells should reduce the likelihood of developing resistant disease and should be applicable to a wide variety of tumor types (Carson-Walter et al.,  Cancer Res.,  2001, 61, 6649-6655).  
       [0003] A comparison of gene expression patterns of endothelial cells derived from blood vessels of normal and malignant colorectal tissues has led to the finding that 46 of the 170 predominantly expressed transcripts were elevated in tumor-associated endothelium (St Croix et al.,  Science,  2000, 289, 1197-1202). Several of these genes encode extracellular matrix proteins but most are of unknown function (St Croix et al.,  Science,  2000, 289, 1197-1202).  
       [0004] The gene known as hypothetical tumor endothelial marker (also known as CDNA FLJ10677 FIS, CLONE NT2RP2006467) is a gene of unknown function which shows a high degree of homology to tumor endothelial marker 6 which was observed to exhibit a high tumor cell to normal cell tag ratio in the aforementioned investigation (St Croix et al.,  Science,  2000, 289, 1197-1202). The finding that hypothetical tumor endothelial marker expression is significantly elevated in tumor cells indicates that modulation of its expression may prove a useful strategy for inhibition of tumor angiogenesis.  
       [0005] Currently, there are no known therapeutic agents that effectively inhibit the synthesis of hypothetical tumor endothelial marker. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting the function of hypothetical tumor endothelial marker.  
       [0006] Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of expression of hypothetical tumor endothelial marker.  
       [0007] The present invention provides compositions and methods for modulating expression of hypothetical tumor endothelial marker.  
       SUMMARY OF THE INVENTION  
       [0008] The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding hypothetical tumor endothelial marker, and which modulate the expression of hypothetical tumor endothelial marker. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of hypothetical tumor endothelial marker in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of hypothetical tumor endothelial marker by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0009] The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding hypothetical tumor endothelial marker, ultimately modulating the amount of hypothetical tumor endothelial marker produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding hypothetical tumor endothelial marker. As used herein, the terms “target nucleic acid” and “nucleic acid encoding hypothetical tumor endothelial marker” encompass DNA encoding hypothetical tumor endothelial marker, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translocation of the RNA to sites within the cell which are distant from the site of RNA synthesis, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of hypothetical tumor endothelial marker. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.  
       [0010] It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding hypothetical tumor endothelial marker. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding hypothetical tumor endothelial marker, regardless of the sequence(s) of such codons.  
       [0011] It is also known in the art that a translation termination codon (or “stop codon”) of a gene may have one of three sequences, i.e., 5′-UAA, 5′-UAG and 5′-UGA (the corresponding DNA sequences are 5′-TAA, 5′-TAG and 5′-TGA, respectively). The terms “start codon region” and “translation initiation codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation initiation codon. Similarly, the terms “stop codon region” and “translation termination codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation termination codon.  
       [0012] The open reading frame (ORF) or “coding region,” which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Other target regions include the 5′ untranslated region (5′UTR), known in the art to refer to the portion of an mRNA in the 5′ direction from the translation initiation codon, and thus including nucleotides between the 5′ cap site and the translation initiation codon of an mRNA or corresponding nucleotides on the gene, and the 3′ untranslated region (3′UTR), known in the art to refer to the portion of an mRNA in the 3′ direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3′ end of an mRNA or corresponding nucleotides on the gene. The 5′ cap of an mRNA comprises an N7-methylated guanosine residue joined to the 5′-most residue of the mRNA via a 5′-5′ triphosphate linkage. The 5′ cap region of an mRNA is considered to include the 5′ cap structure itself as well as the first 50 nucleotides adjacent to the cap. The 5′ cap region may also be a preferred target region.  
       [0013] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as “introns,” which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as “exons” and are spliced together to form a continuous mRNA sequence. mRNA splice sites, i.e., intron-exon junctions, may also be preferred target regions, and are particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular mRNA splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. mRNA transcripts produced via the process of splicing of two (or more) mRNAs from different gene sources are known as “fusion transcripts”. It has also been found that introns can be effective, and therefore preferred, target regions for antisense compounds targeted, for example, to DNA or pre-mRNA.  
       [0014] It is also known in the art that alternative RNA transcripts can be produced from the same genomic region of DNA. These alternative transcripts are generally known as “variants”. More specifically, “pre-mRNA variants” are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and extronic regions.  
       [0015] Upon excision of one or more exon or intron regions or portions thereof during splicing, pre-mRNA variants produce smaller “mRNA variants”. Consequently, mRNA variants are processed pre-mRNA variants and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as “alternative splice variants”. If no splicing of the pre-mRNA variant occurs then the pre-mRNA variant is identical to the mRNA variant.  
       [0016] It is also known in the art that variants can be produced through the use of alternative signals to start or stop transcription and that pre-mRNAs and mRNAs can possess more that one start codon or stop codon. Variants that originate from a pre-mRNA or mRNA that use alternative start codons are known as “alternative start variants” of that pre-mRNA or mRNA. Those transcripts that use an alternative stop codon are known as “alternative stop variants” of that pre-mRNA or mRNA. One specific type of alternative stop variant is the “polyA variant” in which the multiple transcripts produced result from the alternative selection of one of the “polyA stop signals” by the transcription machinery, thereby producing transcripts that terminate at unique polyA sites.  
       [0017] Once one or more target sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect.  
       [0018] In the context of this invention, “hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. “Complementary,” as used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other. Thus, “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable.  
       [0019] An antisense compound is specifically hybridizable when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA to cause a loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed. It is preferred that the antisense compounds of the present invention comprise at least 80% sequence complementarity to a target region within the target nucleic acid, moreover that they comprise 90% sequence complementarity and even more comprise 95% sequence complementarity to the target region within the target nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary, and would therefore specifically hybridize, to a target region would represent 90 percent complementarity. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using basic local alignment search tools (BLAST programs) (Altschul et al.,  J. Mol. Biol.,  1990, 215, 403-410; Zhang and Madden,  Genome Res.,  1997, 7, 649-656).  
       [0020] Antisense and other compounds of the invention, which hybridize to the target and inhibit expression of the target, are identified through experimentation, and representative sequences of these compounds are hereinbelow identified as preferred embodiments of the invention. The sites to which these preferred antisense compounds are specifically hybridizable are hereinbelow referred to as “preferred target regions” and are therefore preferred sites for targeting. As used herein the term “preferred target region” is defined as at least an 8-nucleobase portion of a target region to which an active antisense compound is targeted. While not wishing to be bound by theory, it is presently believed that these target regions represent regions of the target nucleic acid which are accessible for hybridization.  
       [0021] While the specific sequences of particular preferred target regions are set forth below, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred target regions may be identified by one having ordinary skill.  
       [0022] Target regions 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative preferred target regions are considered to be suitable preferred target regions as well.  
       [0023] Exemplary good preferred target regions include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred target regions (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the target region and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly good preferred target regions are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred target regions (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the target region and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art, once armed with the empirically-derived preferred target regions illustrated herein will be able, without undue experimentation, to identify further preferred target regions. In addition, one having ordinary skill in the art will also be able to identify additional compounds, including oligonucleotide probes and primers, that specifically hybridize to these preferred target regions using techniques available to the ordinary practitioner in the art.  
       [0024] Antisense compounds are commonly used as research reagents and diagnostics. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes. Antisense compounds are also used, for example, to distinguish between functions of various members of a biological pathway. Antisense modulation has, therefore, been harnessed for research use.  
       [0025] For use in kits and diagnostics, the antisense compounds of the present invention, either alone or in combination with other antisense compounds or therapeutics, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of a portion or the entire complement of genes expressed within cells and tissues.  
       [0026] Expression patterns within cells or tissues treated with one or more antisense compounds are compared to control cells or tissues not treated with antisense compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.  
       [0027] Examples of methods of gene expression analysis known in the art include DNA arrays or microarrays (Brazma and Vilo,  FEBS Lett.,  2000, 480, 17-24; Celis, et al.,  FEBS Lett.,  2000, 480, 2-16), SAGE (serial analysis of gene expression) (Madden, et al.,  Drug Discov. Today,  2000, 5, 415-425), READS (restriction enzyme amplification of digested cDNAs) (Prashar and Weissman,  Methods Enzymol.,  1999, 303, 258-72), TOGA (total gene expression analysis) (Sutcliffe, et al.,  Proc. Natl. Acad. Sci. U. S. A.,  2000, 97, 1976-81), protein arrays and proteomics (Celis, et al.,  FEBS Lett.,  2000, 480, 2-16; Jungblut, et al.,  Electrophoresis,  1999, 20, 2100-10), expressed sequence tag (EST) sequencing (Celis, et al.,  FEBS Lett.,  2000, 480, 2-16; Larsson, et al.,  J. Biotechnol.,  2000, 80, 143-57), subtractive RNA fingerprinting (SuRF) (Fuchs, et al.,  Anal. Biochem.,  2000, 286, 91-98; Larson, et al.,  Cytometry,  2000, 41, 203-208), subtractive cloning, differential display (DD) (Jurecic and Belmont,  Curr. Opin. Microbiol.,  2000, 3, 316-21), comparative genomic hybridization (Carulli, et al.,  J. Cell Biochem. Suppl.,  1998, 31, 286-96), FISH (fluorescent in situ hybridization) techniques (Going and Gusterson,  Eur. J. Cancer,  1999, 35, 1895-904) and mass spectrometry methods (reviewed in To,  Comb. Chem. High Throughput Screen,  2000, 3, 235-41).  
       [0028] The specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. Antisense oligonucleotide drugs, including ribozymes, have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that oligonucleotides can be useful therapeutic modalities that can be configured to be useful in treatment regimes for treatment of cells, tissues and animals, especially humans.  
       [0029] In the context of this invention, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases.  
       [0030] While antisense oligonucleotides are a preferred form of antisense compound, the present invention comprehends other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics such as are described below. The antisense compounds in accordance with this invention preferably comprise from about 8 to about 80 nucleobases (i.e. from about 8 to about 80 linked nucleosides). Particularly preferred antisense compounds are antisense oligonucleotides from about 8 to about 50 nucleobases, even more preferably those comprising from about 12 to about 30 nucleobases. Antisense compounds include ribozymes, external guide sequence (EGS) oligonucleotides (oligozymes), and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the target nucleic acid and modulate its expression.  
       [0031] Antisense compounds 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative antisense compounds are considered to be suitable antisense compounds as well.  
       [0032] Exemplary preferred antisense compounds include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly preferred antisense compounds are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art, once armed with the empirically-derived preferred antisense compounds illustrated herein will be able, without undue experimentation, to identify further preferred antisense compounds.  
       [0033] Antisense and other compounds of the invention, which hybridize to the target and inhibit expression of the target, are identified through experimentation, and representative sequences of these compounds are herein identified as preferred embodiments of the invention. While specific sequences of the antisense compounds are set forth herein, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred antisense compounds may be identified by one having ordinary skill.  
       [0034] As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2′, 3′ or 5′ hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn, the respective ends of this linear polymeric structure can be further joined to form a circular structure, however, open linear structures are generally preferred. In addition, linear structures may also have internal nucleobase complementarity and may therefore fold in a manner as to produce a double stranded structure. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3′ to 5′ phosphodiester linkage.  
       [0035] Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides.  
       [0036] Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotri-esters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates, 5′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates and borano-phosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3′ to 3′, 5′ to 5′ or 2′ to 2′ linkage. Preferred oligonucleotides having inverted polarity comprise a single 3′ to 3′ linkage at the 3′-most internucleotide linkage i.e. a single inverted nucleoside residue which may be abasic (the nucleobase is missing or has a hydroxyl group in place thereof). Various salts, mixed salts and free acid forms are also included.  
       [0037] Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos.: 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599; 5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.  
       [0038] Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH 2  component parts.  
       [0039] Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos.: 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.  
       [0040] In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos.: 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al.,  Science,  1991, 254, 1497-1500.  
       [0041] Most preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH 2 —NH—O—CH 2 —, —CH 2 —N(CH 3 )—O—CH 2 — [known as a methylene (methylimino) or MMI backbone], —CH 2 —O—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—N(CH 3 )—CH 2 — and —O—N(CH 3 )—CH 2 —CH 2 — [wherein the native phosphodiester backbone is represented as —O—P—O—CH 2 —] of the above referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.  
       [0042] Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2′ position: OH; F; O—, S—, or N-alkyl; O—, S—, or N-alkenyl; O—, S— or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C 1  to C 10  alkyl or C 2  to C 10  alkenyl and alkynyl. Particularly preferred are O[(CH 2 ) n O] m CH 3 , O(CH 2 ) n OCH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 ] 2 , where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2′ position: C 1  to C 10  lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy (2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al.,  Helv. Chim. Acta,  1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in examples hereinbelow, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethyl-amino-ethoxy-ethyl or 2′-DMAEOE), i.e., 2′-O—CH 2 —O—CH 2 —N(CH 3 ) 2 , also described in examples hereinbelow.  
       [0043] Other preferred modifications include 2′-methoxy (2′-O—CH 3 ), 2′-aminopropoxy (2′-OCH 2 CH 2 CH 2 NH 2 ), 2′-allyl (2′-CH 2 —CH═CH 2 ), 2′-O-allyl (2′-O—CH 2 —CH═CH 2 ) and 2′-fluoro (2′-F). The 2′-modification may be in the arabino (up) position or ribo (down) position. A preferred 2′-arabino modification is 2′-F. Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.  
       [0044] A further preferred modification includes Locked Nucleic Acids (LNAs) in which the 2′-hydroxyl group is linked to the 3′ or 4′ carbon atom of the sugar ring thereby forming a bicyclic sugar moiety. The linkage is preferably a methelyne (—CH 2 —) n  group bridging the 2′ oxygen atom and the 4′ carbon atom wherein n is 1 or 2. LNAs and preparation thereof are described in WO 98/39352 and WO 99/14226.  
       [0045] Oligonucleotides may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (—C≡C—CH 3 ) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine(1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g. 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in  The Concise Encyclopedia Of Polymer Science And Engineering,  pages 858-859, Kroschwitz, J. I., ed. John Wiley &amp; Sons, 1990, those disclosed by Englisch et al.,  Angewandte Chemie, International Edition,  1991, 30, 613, and those disclosed by Sanghvi, Y. S., Chapter 15,  Antisense Research and Applications,  pages 289-302, Crooke, S. T. and Lebleu, B. ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds.,  Antisense Research and Applications,  CRC Press, Boca Raton, 1993, pp. 276-278) and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications.  
       [0046] Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.: 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,645,985; 5,830,653; 5,763,588; 6,005,096; and 5,681,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, which is commonly owned with the instant application and also herein incorporated by reference.  
       [0047] Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. The compounds of the invention can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugate groups include cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluores-ceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve oligomer uptake, enhance oligomer resistance to degradation, and/or strengthen sequence-specific hybridization with RNA. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve oligomer uptake, distribution, metabolism or excretion. Representative conjugate groups are disclosed in International Patent Application PCT/US92/09196, filed Oct. 23, 1992 the entire disclosure of which is incorporated herein by reference. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al.,  Proc. Natl. Acad. Sci. USA,  1989, 86, 6553-6556), cholic acid (Manoharan et al.,  Bioorg. Med. Chem. Let.,  1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al.,  Ann. N.Y. Acad. Sci.,  1992, 660, 306-309; Manoharan et al.,  Bioorg. Med. Chem. Let.,  1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al.,  Nucl. Acids Res.,  1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al.,  EMBO J.,  1991, 10, 1111-1118; Kabanov et al.,  FEBS Lett.,  1990, 259, 327-330; Svinarchuk et al.,  Biochimie,  1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,  Tetrahedron Lett.,  1995, 36, 3651-3654; Shea et al.,  Nucl. Acids Res.,  1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al.,  Nucleosides  &amp;  Nucleotides,  1995, 14, 969-973), or adamantane acetic acid (Manoharan et al.,  Tetrahedron Lett.,  1995, 36, 3651-3654), a palmityl moiety (Mishra et al.,  Biochim. Biophys. Acta,  1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al.,  J. Pharmacol. Exp. Ther.,  1996, 277, 923-937). Oligonucleotides of the invention may also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. Oligonucleotide-drug conjugates and their preparation are described in U.S. patent application Ser. No. 09/334,130 (filed Jun. 15, 1999) which is incorporated herein by reference in its entirety.  
       [0048] Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Pat. Nos.: 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference.  
       [0049] It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. The present invention also includes antisense compounds which are chimeric compounds. “Chimeric” antisense compounds or “chimeras,” in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, increased stability and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNAse H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. The cleavage of RNA:RNA hybrids can, in like fashion, be accomplished through the actions of endoribonucleases, such as interferon-induced RNAseL which cleaves both cellular and viral RNA. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.  
       [0050] Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos.: 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.  
       [0051] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.  
       [0052] The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor-targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption-assisting formulations include, but are not limited to, U.S. Pat. Nos.: 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference.  
       [0053] The antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.  
       [0054] The term “prodrug” indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [(S-acetyl-2-thioethyl)phosphate] derivatives according to the methods disclosed in WO 93/24510 to Gosselin et al., published Dec. 9, 1993 or in WO 94/26764 and U.S. Pat. No. 5,770,713 to Imbach et al.  
       [0055] The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.  
       [0056] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., “Pharmaceutical Salts,”  J. of Pharma Sci.,  1977, 66, 1-19). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. As used herein, a “pharmaceutical addition salt” includes a pharmaceutically acceptable salt of an acid form of one of the components of the compositions of the invention. These include organic or inorganic acid salts of the amines. Preferred acid salts are the hydrochlorides, acetates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of a variety of inorganic and organic acids, such as, for example, with inorganic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid; and with amino acids, such as the 20 alpha-amino acids involved in the synthesis of proteins in nature, for example glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible.  
       [0057] For oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine.  
       [0058] The antisense compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of hypothetical tumor endothelial marker is treated by administering antisense compounds in accordance with this invention. The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an antisense compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the antisense compounds and methods of the invention may also be useful prophylactically, e.g., to prevent or delay infection, inflammation or tumor formation, for example. The antisense compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding hypothetical tumor endothelial marker, enabling sandwich and other assays to easily be constructed to exploit this fact. Hybridization of the antisense oligonucleotides of the invention with a nucleic acid encoding hypothetical tumor endothelial marker can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of hypothetical tumor endothelial marker in a sample may also be prepared.  
       [0059] The present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2′-O-methoxyethyl modification are believed to be particularly useful for oral administration.  
       [0060] Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Preferred topical formulations include those in which the oligonucleotides of the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes include neutral (e.g. dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g. dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g. dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA). Oligonucleotides of the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, oligonucleotides may be complexed to lipids, in particular to cationic lipids. Preferred fatty acids and esters include but are not limited arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C 1-10  alkyl ester (e.g. isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof. Topical formulations are described in detail in U.S. patent application Ser. No. 09/315,298 filed on May 20, 1999 which is incorporated herein by reference in its entirety.  
       [0061] Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. Preferred oral formulations are those in which oligonucleotides of the invention are administered in conjunction with one or more penetration enhancers surfactants and chelators. Preferred surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Preferred bile acids/salts include chenodeoxycholic acid (CDCA) and ursodeoxychenodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodihydrofusidate. Preferred fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g. sodium). Also preferred are combinations of penetration enhancers, for example, fatty acids/salts in combination with bile acids/salts. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. Oligonucleotides of the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. Oligonucleotide complexing agents include poly-amino acids; polyimines; polyacrylates; polyalkylacrylates, polyoxethanes, polyalkylcyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylates; DEAE-derivatized polyimines, pollulans, celluloses and starches. Particularly preferred complexing agents include chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylamino-methylethylene P(TDAE), polyaminostyrene (e.g. p-amino), poly(methylcyanoacrylate), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-glycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for oligonucleotides and their preparation are described in detail in U.S. application Ser. Nos. 08/886,829 (filed Jul. 1, 1997), 09/108,673 (filed Jul. 1, 1998), 09/256,515 (filed Feb. 23, 1999), 09/082,624 (filed May 21, 1998) and 09/315,298 (filed May 20, 1999), each of which is incorporated herein by reference in their entirety.  
       [0062] Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.  
       [0063] Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.  
       [0064] The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.  
       [0065] The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.  
       [0066] In one embodiment of the present invention the pharmaceutical compositions may be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the compositions of the present invention.  
       [0067] Emulsions  
       [0068] The compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter (Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in  Remington&#39;s Pharmaceutical Sciences,  Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion.  
       [0069] Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).  
       [0070] Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (Rieger, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285).  
       [0071] Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate.  
       [0072] A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).  
       [0073] Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase.  
       [0074] Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.  
       [0075] The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions.  
       [0076] In one embodiment of the present invention, the compositions of oligonucleotides and nucleic acids are formulated as microemulsions. A microemulsion may be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in:  Controlled Release of Drugs: Polymers and Aggregate Systems,  Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in  Remington&#39;s Pharmaceutical Sciences,  Mack Publishing Co., Easton, Pa., 1985, p. 271).  
       [0077] The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously.  
       [0078] Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DA0750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C 8 -C 10  glycerides, vegetable oils and silicone oil.  
       [0079] Microemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al.,  Pharmaceutical Research,  1994, 11, 1385-1390; Ritschel,  Meth. Find. Exp. Clin. Pharmacol.,  1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al.,  Pharmaceutical Research,  1994, 11, 1385; Ho et al.,  J. Pharm. Sci.,  1996, 85, 138-143). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or oligonucleotides. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of oligonucleotides and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of oligonucleotides and nucleic acids within the gastrointestinal tract, vagina, buccal cavity and other areas of administration.  
       [0080] Microemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the oligonucleotides and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categories—surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p. 92). Each of these classes has been discussed above.  
       [0081] Liposomes  
       [0082] There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers.  
       [0083] Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo.  
       [0084] In order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores.  
       [0085] Further advantages of liposomes include; liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes.  
       [0086] Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomes start to merge with the cellular membranes and as the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act.  
       [0087] Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side-effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer a wide variety of drugs, both hydrophilic and hydrophobic, into the skin.  
       [0088] Several reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis.  
       [0089] Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al.,  Biochem. Biophys. Res. Commun.,  1987, 147, 980-985).  
       [0090] Liposomes which are pH-sensitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al.,  Journal of Controlled Release,  1992, 19, 269-274).  
       [0091] One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol.  
       [0092] Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes sores while delivery of interferon via other means (e.g. as a solution or as an emulsion) were ineffective (Weiner et al.,  Journal of Drug Targeting,  1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al.,  Antiviral Research,  1992, 18, 259-265).  
       [0093] Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome™ I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin (Hu et al.  S.T.P.Pharma. Sci.,  1994, 4, 6, 466).  
       [0094] Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al.,  FEBS Letters,  1987, 223, 42; Wu et al.,  Cancer Research,  1993, 53, 3765).  
       [0095] Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. ( Ann. N.Y. Acad. Sci.,  1987, 507, 64) reported the ability of monosialoganglioside G M1 , galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. ( Proc. Natl. Acad. Sci. U.S.A.,  1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G M1  or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97/13499 (Lim et al.).  
       [0096] Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. ( Bull. Chem. Soc. Jpn.,  1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C 12 15G, that contains a PEG moiety. Illum et al. ( FEBS Lett.,  1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. ( FEBS Lett.,  1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. ( Biochimica et Biophysica Acta,  1990, 1029, 91) extended such observations to other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Patent No. EP 0 445 131 B1 and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 B1). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94/20073 (Zalipsky et al.) Liposomes comprising PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al.). U.S. Pat. Nos. 5,540,935 (Miyazaki et al.) and 5,556,948 (Tagawa et al.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces.  
       [0097] A limited number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include an antisense RNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al. discloses liposomes comprising antisense oligonucleotides targeted to the raf gene.  
       [0098] Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g. they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfersome-mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin.  
       [0099] Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group (also known as the “head”) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in  Pharmaceutical Dosage Forms,  Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).  
       [0100] If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class.  
       [0101] If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are the alkyl sulfates and the soaps.  
       [0102] If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class.  
       [0103] If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkylamides, N-alkylbetaines and phosphatides.  
       [0104] The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in  Pharmaceutical Dosage Forms,  Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).  
       [0105] Penetration Enhancers  
       [0106] In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs may cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs.  
       [0107] Penetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p.92). Each of the above mentioned classes of penetration enhancers are described below in greater detail.  
       [0108] Surfactants: In connection with the present invention, surfactants (or “surface-active agents”) are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of oligonucleotides through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p.92); and perfluorochemical emulsions, such as FC-43. Takahashi et al.,  J. Pharm. Pharmacol.,  1988, 40, 252).  
       [0109] Fatty acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, C 1-10  alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p.92; Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654).  
       [0110] Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman &amp; Gilman&#39;s  The Pharmacological Basis of Therapeutics,  9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus the term “bile salts” includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. The bile salts of the invention include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, page 92; Swinyard, Chapter 39 In:  Remington&#39;s Pharmaceutical Sciences,  18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33; Yamamoto et al.,  J. Pharm. Exp. Ther.,  1992, 263, 25; Yamashita et al.,  J. Pharm. Sci.,  1990, 79, 579-583).  
       [0111] Chelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of oligonucleotides through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett,  J. Chromatogr.,  1993, 618, 315-339). Chelating agents of the invention include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines)(Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, page 92; Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33; Buur et al.,  J. Control Rel.,  1990, 14, 43-51).  
       [0112] Non-chelating non-surfactants: As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of oligonucleotides through the alimentary mucosa (Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al.,  J. Pharm. Pharmacol.,  1987, 39, 621-626).  
       [0113] Agents that enhance uptake of oligonucleotides at the cellular level may also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97/30731), are also known to enhance the cellular uptake of oligonucleotides.  
       [0114] Other agents may be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone.  
       [0115] Carriers  
       [0116] Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, “carrier compound” or “carrier” can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate oligonucleotide in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4′isothiocyano-stilbene-2,2′-disulfonic acid (Miyao et al.,  Antisense Res. Dev.,  1995, 5, 115-121; Takakura et al.,  Antisense  &amp;  Nucl. Acid Drug Dev.,  1996, 6, 177-183).  
       [0117] Excipients  
       [0118] In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc.).  
       [0119] Pharmaceutically acceptable organic or inorganic excipient suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.  
       [0120] Formulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used.  
       [0121] Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.  
       [0122] Other Components  
       [0123] The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.  
       [0124] Aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.  
       [0125] Certain embodiments of the invention provide pharmaceutical compositions containing (a) one or more antisense compounds and (b) one or more other chemotherapeutic agents which function by a non-antisense mechanism. Examples of such chemotherapeutic agents include but are not limited to daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine arabinoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxycoformycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colchicine, taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate, irinotecan, topotecan, gemcitabine, teniposide, cisplatin and diethylstilbestrol (DES). See, generally,  The Merck Manual of Diagnosis and Therapy,  15th Ed. 1987, pp. 1206-1228, Berkow et al., eds., Rahway, N.J. When used with the compounds of the invention, such chemotherapeutic agents may be used individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide for a period of time followed by MTX and oligonucleotide), or in combination with one or more other such chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and oligonucleotide). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirin, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention. See, generally,  The Merck Manual-of Diagnosis and Therapy,  15th Ed., Berkow et al., eds., 1987, Rahway, N.J., pages 2499-2506 and 46-49, respectively). Other non-antisense chemotherapeutic agents are also within the scope of this invention. Two or more combined compounds may be used together or sequentially.  
       [0126] In another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially.  
       [0127] The formulation of therapeutic compositions and their subsequent administration is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC 50 s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ug to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years.  
       [0128] While the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same.  
     
    
    
     EXAMPLES  
     Example 1  
     [0129] Nucleoside Phosphoramidites for Oligonucleotide Synthesis Deoxy and 2′-alkoxy amidites  
     [0130] 2′-Deoxy and 2′-methoxy beta-cyanoethyldiisopropyl phosphoramidites were purchased from commercial sources (e.g. Chemgenes, Needham Mass. or Glen Research, Inc. Sterling Va.). Other 2′-O-alkoxy substituted nucleoside amidites are prepared as described in U.S. Pat. No. 5,506,351, herein incorporated by reference. For oligonucleotides synthesized using 2′-alkoxy amidites, optimized synthesis cycles were developed that incorporate multiple steps coupling longer wait times relative to standard synthesis cycles.  
     [0131] The following abbreviations are used in the text: thin layer chromatography (TLC), melting point (MP), high pressure liquid chromatography (HPLC), Nuclear Magnetic Resonance (NMR), argon (Ar), methanol (MeOH), dichloromethane (CH 2 Cl 2 ), triethylamine (TEA), dimethyl formamide (DMF), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF).  
     [0132] Oligonucleotides containing 5-methyl-2′-deoxycytidine (5-Me-dC)nucleotides were synthesized according to published methods (Sanghvi, et. al.,  Nucleic Acids Research,  1993, 21, 3197-3203) using commercially available phosphoramidites (Glen Research, Sterling Va. or ChemGenes, Needham Mass.) or prepared as follows:  
     [0133] Preparation of 5′-O-Dimethoxytrityl-thymidine intermediate for 5-methyl dC amidite  
     [0134] To a 50 L glass reactor equipped with air stirrer and Ar gas line was added thymidine (1.00 kg, 4.13 mol) in anhydrous pyridine (6 L) at ambient temperature. Dimethoxytrityl (DMT) chloride (1.47 kg, 4.34 mol. 1.05 eq) was added as a solid in four portions over 1 h. After 30 min, TLC indicated approx. 95% product, 2% thymidine, 5% DMT reagent and by-products and 2% 3′,5′-bis DMT product (R f  in EtOAc 0.45, 0.05, 0.98, 0.95 respectively). Saturated sodium bicarbonate (4 L) and CH 2 Cl 2  were added with stirring (pH of the aqueous layer 7.5). An additional 18 L of water was added, the mixture was stirred, the phases were separated, and the organic layer was transferred to a second 50 L vessel. The aqueous layer was extracted with additional CH 2 Cl 2  (2×2 L). The combined organic layer was washed with water (10 L) and then concentrated in a rotary evaporator to approx. 3.6 kg total weight. This was redissolved in CH 2 Cl 2  (3.5 L), added to the reactor followed by water (6 L) and hexanes (13 L). The mixture was vigorously stirred and seeded to give a fine white suspended solid starting at the interface. After stirring for 1 h, the suspension was removed by suction through a ½″ diameter teflon tube into a 20 L suction flask, poured onto a 25 cm Coors Buchner funnel, washed with water (2×3 L) and a mixture of hexanes-CH 2 Cl 2  (4:1, 2×3 L) and allowed to air dry overnight in pans (1″ deep). This was further dried in a vacuum oven (75° C., 0.1 mm Hg, 48 h) to a constant weight of 2072 g (93%) of a white solid, (mp 122-124° C.). TLC indicated a trace contamination of the bis DMT product. NMR spectroscopy also indicated that 1-2 mole percent pyridine and about 5 mole percent of hexanes was still present.  
     [0135] Preparation of 51-O-Dimethoxytrityl-2′-deoxy-5-methylcytidine intermediate for 5-methyl-dC amidite  
     [0136] To a 50 L Schott glass-lined steel reactor equipped with an electric stirrer, reagent addition pump (connected to an addition funnel), heating/cooling system, internal thermometer and an Ar gas line was added 5′-O-dimethoxytrityl-thymidine (3.00 kg, 5.51 mol), anhydrous acetonitrile (25 L) and TEA (12.3 L, 88.4 mol, 16 eq). The mixture was chilled with stirring to −10° C. internal temperature (external −20° C.). Trimethylsilylchloride (2.1 L, 16.5 mol, 3.0 eq) was added over 30 minutes while maintaining the internal temperature below −5° C., followed by a wash of anhydrous acetonitrile (1 L). Note: the reaction is mildly exothermic and copious hydrochloric acid fumes form over the course of the addition. The reaction was allowed to warm to 0° C. and the reaction progress was confirmed by TLC (EtOAc-hexanes 4:1; R f  0.43 to 0.84 of starting material and silyl product, respectively). Upon completion, triazole (3.05 kg, 44 mol, 8.0 eq) was added the reaction was cooled to −20° C. internal temperature (external −30° C.). Phosphorous oxychloride (1035 mL, 11.1 mol, 2.01 eq) was added over 60 min so as to maintain the temperature between −20° C. and −10° C. during the strongly exothermic process, followed by a wash of anhydrous acetonitrile (1 L). The reaction was warmed to 0° C. and stirred for 1 h. TLC indicated a complete conversion to the triazole product (R f  0.83 to 0.34 with the product spot glowing in long wavelength UV light). The reaction mixture was a peach-colored thick suspension, which turned darker red upon warming without apparent decomposition. The reaction was cooled to −15° C. internal temperature and water (5 L) was slowly added at a rate to maintain the temperature below +10° C. in order to quench the reaction and to form a homogenous solution. (Caution: this reaction is initially very strongly exothermic). Approximately one-half of the reaction volume (22 L) was transferred by air pump to another vessel, diluted with EtOAc (12 L) and extracted with water (2×8 L). The combined water layers were back-extracted with EtOAc (6 L). The water layer was discarded and the organic layers were concentrated in a 20 L rotary evaporator to an oily foam. The foam was coevaporated with anhydrous acetonitrile (4 L) to remove EtOAc. (note: dioxane may be used instead of anhydrous acetonitrile if dried to a hard foam). The second half of the reaction was treated in the same way. Each residue was dissolved in dioxane (3 L) and concentrated ammonium hydroxide (750 mL) was added. A homogenous solution formed in a few minutes and the reaction was allowed to stand overnight (although the reaction is complete within 1 h).  
     [0137] TLC indicated a complete reaction (product R f  0.35 in EtOAc-MeOH 4:1). The reaction solution was concentrated on a rotary evaporator to a dense foam. Each foam was slowly redissolved in warm EtOAc (4 L; 50° C.), combined in a 50 L glass reactor vessel, and extracted with water (2×4L) to remove the triazole by-product. The water was back-extracted with EtOAc (2 L). The organic layers were combined and concentrated to about 8 kg total weight, cooled to 0° C. and seeded with crystalline product. After 24 hours, the first crop was collected on a 25 cm Coors Buchner funnel and washed repeatedly with EtOAc (3×3L) until a white powder was left and then washed with ethyl ether (2×3L). The solid was put in pans (1″ deep) and allowed to air dry overnight. The filtrate was concentrated to an oil, then redissolved in EtOAc (2 L), cooled and seeded as before. The second crop was collected and washed as before (with proportional solvents) and the filtrate was first extracted with water (2×1L) and then concentrated to an oil. The residue was dissolved in EtOAc (1 L) and yielded a third crop which was treated as above except that more washing was required to remove a yellow oily layer.  
     [0138] After air-drying, the three crops were dried in a vacuum oven (50° C., 0.1 mm Hg, 24 h) to a constant weight (1750, 600 and 200 g, respectively) and combined to afford 2550 g (85%) of a white crystalline product (MP 215-217° C.) when TLC and NMR spectroscopy indicated purity. The mother liquor still contained mostly product (as determined by TLC) and a small amount of triazole (as determined by NMR spectroscopy), bis DMT product and unidentified minor impurities. If desired, the mother liquor can be purified by silica gel chromatography using a gradient of MeOH (0-25%) in EtOAc to further increase the yield.  
     [0139] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-N4-benzoyl-5-methylcytidine penultimate intermediate for 5-methyl dC amidite  
     [0140] Crystalline 51-O-dimethoxytrityl-5-methyl-21-deoxycytidine (2000 g, 3.68 mol) was dissolved in anhydrous DMF (6.0 kg) at ambient temperature in a 50 L glass reactor vessel equipped with an air stirrer and argon line. Benzoic anhydride (Chem Impex not Aldrich, 874 g, 3.86 mol, 1.05 eq) was added and the reaction was stirred at ambient temperature for 8 h. TLC (CH 2 Cl 2 -EtOAc; CH 2 Cl 2 -EtOAc 4:1; R f  0.25) indicated approx. 92% complete reaction. An additional amount of benzoic anhydride (44 g, 0.19 mol) was added. After a total of 18 h, TLC indicated approx. 96% reaction completion. The solution was diluted with EtOAc (20 L), TEA (1020 mL, 7.36 mol, ca 2.0 eq) was added with stirring, and the mixture was extracted with water (15 L, then 2×10 L). The aqueous layer was removed (no back-extraction was needed) and the organic layer was concentrated in 2×20 L rotary evaporator flasks until a foam began to form. The residues were coevaporated with acetonitrile (1.5 L each) and dried (0.1 mm Hg, 25° C., 24 h) to 2520 g of a dense foam. High pressure liquid chromatography (HPLC) revealed a contamination of 6.3% of N4, 3′-O-dibenzoyl product, but very little other impurities.  
     [0141] THe product was purified by Biotage column chromatography (5 kg Biotage) prepared with 65:35:1 hexanes-EtOAc-TEA (4L). The crude product (800 g),dissolved in CH 2 Cl 2  (2 L), was applied to the column. The column was washed with the 65:35:1 solvent mixture (20 kg), then 20:80:1 solvent mixture (10 kg), then 99:1 EtOAc:TEA (17 kg). The fractions containing the product were collected, and any fractions containing the product and impurities were retained to be resubjected to column chromatography. The column was reequilibrated with the original 65:35:1 solvent mixture (17 kg). A second batch of crude product (840 g) was applied to the column as before. The column was washed with the following solvent gradients: 65:35:1 (9 kg), 55:45:1 (20 kg), 20:80:1 (10 kg), and 99:1 EtOAc:TEA(15 kg). The column was reequilibrated as above, and a third batch of the crude product (850 g) plus impure fractions recycled from the two previous columns (28 g) was purified following the procedure for the second batch. The fractions containing pure product combined and concentrated on a 20L rotary evaporator, co-evaporated with acetontirile (3 L) and dried (0.1 mm Hg, 48 h, 25° C.) to a constant weight of 2023 g (85%) of white foam and 20 g of slightly contaminated product from the third run. HPLC indicated a purity of 99.8% with the balance as the diBenzoyl product.  
     [0142] [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N4-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (5-methyl dC amidite)  
     [0143] 5′-0-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N 4 -benzoyl-5-methylcytidine (998 g, 1.5 mol) was dissolved in anhydrous DMF (2 L). The solution was co-evaporated with toluene (300 ml) at 50° C. under reduced pressure, then cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (52.5 g, 0.75 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (15 ml) was added and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (2.5 L) and water (600 ml), and extracted with hexane (3×3 L). The mixture was diluted with water (1.2 L) and extracted with a mixture of toluene (7.5 L) and hexane (6 L). The two layers were separated, the upper layer was washed with DMF-water (7:3 v/v, 3×2 L) and water (3×2 L), and the phases were separated. The organic layer was dried (Na 2 SO 4 ), filtered and rotary evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried to a constant weight (25° C., 0.1 mm Hg, 40 h) to afford 1250 g an off-white foam solid (96%).  
     [0144] 2′-Fluoro amidites  
     [0145] 21-Fluorodeoxyadenosine amidites  
     [0146] 2′-fluoro oligonucleotides were synthesized as described previously [Kawasaki, et. al.,  J. Med. Chem.,  1993, 36, 831-841] and U.S. Pat. No. 5,670,633, herein incorporated by reference. The preparation of 2′-fluoropyrimidines containing a 5-methyl substitution are described in U.S. Pat. No. 5,861,493. Briefly, the protected nucleoside N6-benzoyl-2′-deoxy-2′-fluoroadenosine was synthesized utilizing commercially available 9-beta-D-arabinofuranosyladenine as starting material and whereby the 2′-alpha-fluoro atom is introduced by a S N 2-displacement of a 2′-beta-triflate group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine was selectively protected in moderate yield as the 3′,5′-ditetrahydropyranyl (THP) intermediate. Deprotection of the THP and N6-benzoyl groups was accomplished using standard methodologies to obtain the 5′-dimethoxytrityl-(DMT) and 5′-DMT-3′-phosphoramidite intermediates.  
     [0147] 2′-Fluorodeoxyguanosine  
     [0148] The synthesis of 2′-deoxy-2′-fluoroguanosine was accomplished using tetraisopropyldisiloxanyl (TPDS) protected 9-beta-D-arabinofuranosylguanine as starting material, and conversion to the intermediate isobutyryl-arabinofuranosylguanosine. Alternatively, isobutyryl-arabinofuranosylguanosine was prepared as described by Ross et al., (Nucleosides &amp; Nucleosides, 16, 1645, 1997). Deprotection of the TPDS group was followed by protection of the hydroxyl group with THP to give isobutyryl di-THP protected arabinofuranosylguanine. Selective O-deacylation and triflation was followed by treatment of the crude product with fluoride, then deprotection of the THP groups. Standard methodologies were used to obtain the 5′-DMT- and 5′-DMT-3′-phosphoramidites.  
     [0149] 2′-Fluorouridine  
     [0150] Synthesis of 2′-deoxy-2′-fluorouridine was accomplished by the modification of a literature procedure in which 2,2′-anhydro-1-beta-D-arabinofuranosyluracil was treated with 70% hydrogen fluoride-pyridine. Standard procedures were used to obtain the 5′-DMT and 5′-DMT-3′phosphoramidites.  
     [0151] 2′-Fluorodeoxycytidine  
     [0152] 2′-deoxy-2′-fluorocytidine was synthesized via amination of 2′-deoxy-2′-fluorouridine, followed by selective protection to give N4-benzoyl-2′-deoxy-2′-fluorocytidine. Standard procedures were used to obtain the 5′-DMT and 5′-DMT-3′phosphoramidites.  
     [0153] 2′-O-(2-Methoxyethyl) modified amidites  
     [0154] 2′-O-Methoxyethyl-substituted nucleoside amidites (otherwise known as MOE amidites) are prepared as follows, or alternatively, as per the methods of Martin, P., (Helvetica Chimica Acta, 1995, 78, 486-504).  
     [0155] Preparation of 2′-O-(2-methoxyethyl)-5-methyluridine intermediate  
     [0156] 2,2′-Anhydro-5-methyl-uridine (2000 g, 8.32 mol), tris(2-methoxyethyl)borate (2504 g, 10.60 mol), sodium bicarbonate (60 g, 0.70 mol) and anhydrous 2-methoxyethanol (5 L) were combined in a 12 L three necked flask and heated to 130° C. (internal temp) at atmospheric pressure, under an argon atmosphere with stirring for 21 h. TLC indicated a complete reaction. The solvent was removed under reduced pressure until a sticky gum formed (50-85° C. bath temp and 100-11 mm Hg) and the residue was redissolved in water (3 L) and heated to boiling for 30 min in order the hydrolyze the borate esters. The water was removed under reduced pressure until a foam began to form and then the process was repeated. HPLC indicated about 77% product, 15% diner (5′ of product attached to 2′ of starting material) and unknown derivatives, and the balance was a single unresolved early eluting peak.  
     [0157] The gum was redissolved in brine (3 L), and the flask was rinsed with additional brine (3 L). The combined aqueous solutions were extracted with chloroform (20 L) in a heavier-than continuous extractor for 70 h. The chloroform layer was concentrated by rotary evaporation in a 20 L flask to a sticky foam (2400 g). This was coevaporated with MeOH (400 mL) and EtOAc (8 L) at 75° C. and 0.65 atm until the foam dissolved at which point the vacuum was lowered to about 0.5 atm. After 2.5 L of distillate was collected a precipitate began to form and the flask was removed from the rotary evaporator and stirred until the suspension reached ambient temperature. EtOAc (2 L) was added and the slurry was filtered on a 25 cm table top Buchner funnel and the product was washed with EtOAc (3×2 L). The bright white solid was air dried in pans for 24 h then further dried in a vacuum oven (50° C., 0.1 mm Hg, 24 h) to afford 1649 g of a white crystalline solid (mp 115.5-116.5° C.).  
     [0158] The brine layer in the 20 L continuous extractor was further extracted for 72 h with recycled chloroform. The chloroform was concentrated to 120 g of oil and this was combined with the mother liquor from the above filtration (225 g), dissolved in brine (250 mL) and extracted once with chloroform (250 mL). The brine solution was continuously extracted and the product was crystallized as described above to afford an additional 178 g of crystalline product containing about 2% of thymine. The combined yield was 1827 g (69.4%). HPLC indicated about 99.5% purity with the balance being the dimer.  
     [0159] Preparation of 51-O-DMT-2′-O-(2-methoxyethyl)-5-methyluridine penultimate intermediate  
     [0160] In a 50 L glass-lined steel reactor, 21-O-(2-methoxyethyl)-5-methyl-uridine (MOE-T, 1500 g, 4.738 mol), lutidine (1015 g, 9.476 mol) were dissolved in anhydrous acetonitrile (15 L). The solution was stirred rapidly and chilled to −10° C. (internal temperature). Dimethoxytriphenylmethyl chloride (1765.7 g, 5.21 mol) was added as a solid in one portion. The reaction was allowed to warm to −2° C. over 1 h. (Note: The reaction was monitored closely by TLC (EtOAc) to determine when to stop the reaction so as to not generate the undesired bis-DMT substituted side product). The reaction was allowed to warm from −2 to 3° C. over 25 min. then quenched by adding MeOH (300 mL) followed after 10 min by toluene (16 L) and water (16 L). The solution was transferred to a clear 50 L vessel with a bottom outlet, vigorously stirred for 1 minute, and the layers separated. The aqueous layer was removed and the organic layer was washed successively with 10% aqueous citric acid (8 L) and water (12 L). The product was then extracted into the aqueous phase by washing the toluene solution with aqueous sodium hydroxide (0.5N, 16 L and 8 L). The combined aqueous layer was overlayed with toluene (12 L) and solid citric acid (8 moles, 1270 g) was added with vigorous stirring to lower the pH of the aqueous layer to 5.5 and extract the product into the toluene. The organic layer was washed with water (10 L) and TLC of the organic layer indicated a trace of DMT-O-Me, bis DMT and diner DMT.  
     [0161] The toluene solution was applied to a silica gel column (6 L sintered glass funnel containing approx. 2 kg of silica gel slurried with toluene (2 L) and TEA(25 mL)) and the fractions were eluted with toluene (12 L) and EtOAc (3×4 L) using vacuum applied to a filter flask placed below the column. The first EtOAc fraction containing both the desired product and impurities were resubjected to column chromatography as above. The clean fractions were combined, rotary evaporated to a foam, coevaporated with acetonitrile (6 L) and dried in a vacuum oven (0.1 mm Hg, 40 h, 40° C.) to afford 2850 g of a white crisp foam. NMR spectroscopy indicated a 0.25 mole % remainder of acetonitrile (calculates to be approx. 47 g) to give a true dry weight of 2803 g (96%). HPLC indicated that the product was 99.41% pure, with the remainder being 0.06 DMT-O-Me, 0.10 unknown, 0.44 bis DMT, and no detectable dimer DMT or 3′-O-DMT.  
     [0162] Preparation of [5,-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T amidite)  
     [0163] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1237 g, 2.0 mol) was dissolved in anhydrous DMF (2.5 L). The solution was co-evaporated with toluene (200 ml) at 50° C. under reduced pressure, then cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (900 g, 3.0 mol) and tetrazole (70 g, 1.0 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (20 ml) was added and the solution was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (3.5 L) and water (600 ml) and extracted with hexane (3×3L). The mixture was diluted with water (1.6 L) and extracted with the mixture of toluene (12 L) and hexanes (9 L). The upper layer was washed with DMF-water (7:3 v/v, 3×3 L) and water (3×3 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1526 g of an off-white foamy solid (95%).  
     [0164] Preparation of 5′-O-Dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methylcytidine intermediate  
     [0165] To a 50 L Schott glass-lined steel reactor equipped with an electric stirrer, reagent addition pump (connected to an addition funnel), heating/cooling system, internal thermometer and argon gas line was added 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methyl-uridine (2.616 kg, 4.23 mol, purified by base extraction only and no scrub column), anhydrous acetonitrile (20 L), and TEA (9.5 L, 67.7 mol, 16 eq). The mixture was chilled with stirring to −10° C. internal temperature (external −20° C.). Trimethylsilylchloride (1.60 L, 12.7 mol, 3.0 eq) was added over 30 min. while maintaining the internal temperature below −5° C., followed by a wash of anhydrous acetonitrile (1 L). (Note: the reaction is mildly exothermic and copious hydrochloric acid fumes form over the course of the addition). The reaction was allowed to warm to 0° C. and the reaction progress was confirmed by TLC (EtOAc, R f  0.68 and 0.87 for starting material and silyl product, respectively). Upon completion, triazole (2.34 kg, 33.8 mol, 8.0 eq) was added the reaction was cooled to −20° C. internal temperature (external −30° C.). Phosphorous oxychloride (793 mL, 8.51 mol, 2.01 eq) was added slowly over 60 min so as to maintain the temperature between −20° C. and −10° C. (note: strongly exothermic), followed by a wash of anhydrous acetonitrile (1 L). The reaction was warmed to 0° C. and stirred for 1 h, at which point it was an off-white thick suspension. TLC indicated a complete conversion to the triazole product (EtOAc, R f  0.87 to 0.75 with the product spot glowing in long wavelength UV light). The reaction was cooled to −15° C. and water (5 L) was slowly added at a rate to maintain the temperature below +10° C. in order to quench the reaction and to form a homogenous solution. (Caution: this reaction is initially very strongly exothermic). Approximately one-half of the reaction volume (22 L) was transferred by air pump to another vessel, diluted with EtOAc (12 L) and extracted with water (2×8 L). The second half of the reaction was treated in the same way. The combined aqueous layers were back-extracted with EtOAc (8 L) The organic layers were combined and concentrated in a 20 L rotary evaporator to an oily foam. The foam was coevaporated with anhydrous acetonitrile (4 L) to remove EtOAc. (note: dioxane may be used instead of anhydrous acetonitrile if dried to a hard foam). The residue was dissolved in dioxane (2 L) and concentrated ammonium hydroxide (750 mL) was added. A homogenous solution formed in a few minutes and the reaction was allowed to stand overnight  
     [0166] TLC indicated a complete reaction (CH 2 Cl 2 -acetone-MeOH, 20:5:3, R f  0. 51). The reaction solution was concentrated on a rotary evaporator to a dense foam and slowly redissolved in warm CH 2 Cl 2  (4 L, 40° C.) and transferred to a 20 L glass extraction vessel equipped with a air-powered stirrer. The organic layer was extracted with water (2×6 L) to remove the triazole by-product. (Note: In the first extraction an emulsion formed which took about 2 h to resolve). The water layer was back-extracted with CH 2 Cl 2  (2×2 L), which in turn was washed with water (3 L). The combined organic layer was concentrated in 2×20 L flasks to a gum and then recrystallized from EtOAc seeded with crystalline product. After sitting overnight, the first crop was collected on a 25 cm Coors Buchner funnel and washed repeatedly with EtOAc until a white free-flowing powder was left (about 3×3 L). The filtrate was concentrated to an oil recrystallized from EtOAc, and collected as above. The solid was air-dried in pans for 48 h, then further dried in a vacuum oven (50° C., 0.1 mm Hg, 17 h) to afford 2248 g of a bright white, dense solid (86%). An HPLC analysis indicated both crops to be 99.4% pure and NMR spectroscopy indicated only a faint trace of EtOAc remained.  
     [0167] Preparation of 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-N4-benzoyl-5-methyl-cytidine penultimate intermediate:  
     [0168] Crystalline 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methyl-cytidine (1000 g, 1.62 mol) was suspended in anhydrous DMF (3 kg) at ambient temperature and stirred under an Ar atmosphere. Benzoic anhydride (439.3 g, 1.94 mol) was added in one portion. The solution clarified after 5 hours and was stirred for 16 h. HPLC indicated 0.45% starting material remained (as well as 0.32% N4, 3′-O-bis Benzoyl). An additional amount of benzoic anhydride (6.0 g, 0.0265 mol) was added and after 17 h, HPLC indicated no starting material was present. TEA (450 mL, 3.24 mol) and toluene (6 L) were added with stirring for 1 minute. The solution was washed with water (4×4 L), and brine (2×4 L). The organic layer was partially evaporated on a 20 L rotary evaporator to remove 4 L of toluene and traces of water. HPLC indicated that the bis benzoyl side product was present as a 6% impurity. The residue was diluted with toluene (7 L) and anhydrous DMSO (200 mL, 2.82 mol) and sodium hydride (60% in oil, 70 g, 1.75 mol) was added in one portion with stirring at ambient temperature over 1 h. The reaction was quenched by slowly adding then washing with aqueous citric acid (10%, 100 mL over 10 min, then 2×4 L), followed by aqueous sodium bicarbonate (2%, 2 L), water (2×4 L) and brine (4 L). The organic layer was concentrated on a 20 L rotary evaporator to about 2 L total volume. The residue was purified by silica gel column chromatography (6 L Buchner funnel containing 1.5 kg of silica gel wetted with a solution of EtOAc-hexanes-TEA(70:29:1)). The product was eluted with the same solvent (30 L) followed by straight EtOAc (6 L). The fractions containing the product were combined, concentrated on a rotary evaporator to a foam and then dried in a vacuum oven (50° C., 0.2 mm Hg, 8 h) to afford 1155 g of a crisp, white foam (98%). HPLC indicated a purity of &gt;99.7%.  
     [0169] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE 5-Me-C amidite)  
     [0170] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2-O-(2-methoxyethyl)-N 4 -benzoyl-5-methylcytidine (1082 g, 1.5 mol) was dissolved in anhydrous DMF (2 L) and co-evaporated with toluene (300 ml) at 50° C. under reduced pressure. The mixture was cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (52.5 g, 0.75 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (1 L) and water (400 ml) and extracted with hexane (3×3 L). The mixture was diluted with water (1.2 L) and extracted with a mixture of toluene (9 L) and hexanes (6 L). The two layers were separated and the upper layer was washed with DMF-water (60:40 v/v, 3×3 L) and water (3×2 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1336 g of an off-white foam (97%).  
     [0171] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 6 -benzoyladenosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE A amdite)  
     [0172] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 6 -benzoyladenosine (purchased from Reliable Biopharmaceutical, St. Lois, Mo.), 1098 g, 1.5 mol) was dissolved in anhydrous DMF (3 L) and co-evaporated with toluene (300 ml) at 50° C. The mixture was cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (78.8 g, 1.24 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (1 L) and water (400 ml) and extracted with hexanes (3×3 L). The mixture was diluted with water (1.4 L) and extracted with the mixture of toluene (9 L) and hexanes (6 L). The two layers were separated and the upper layer was washed with DMF-water (60:40, v/v, 3×3 L) and water (3×2 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated to a sticky foam. The residue was co-evaporated with acetonitrile (2.5 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1350 g of an off-white foam solid (96%).  
     [0173] Prepartion of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -isobutyrylguanosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (NOE G amidite)  
     [0174] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -isobutyrlguanosine (purchased from Reliable Biopharmaceutical, St. Louis, Mo., 1426 g, 2.0 mol) was dissolved in anhydrous DMF (2 L). The solution was co-evaporated with toluene (200 ml) at 50° C., cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (900 g, 3.0 mol) and tetrazole (68 g, 0.97 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (2 L) and water (600 ml) and extracted with hexanes (3×3 L). The mixture was diluted with water (2 L) and extracted with a mixture of toluene (10 L) and hexanes (5 L). The two layers were separated and the upper layer was washed with DMF-water (60:40, v/v, 3×3 L). EtOAc (4 L) was added and the solution was washed with water (3×4 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated to approx. 4 kg. Hexane (4 L) was added, the mixture was shaken for 10 min, and the supernatant liquid was decanted. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1660 g of an off-white foamy solid (91%).  
     [0175] 2′-O-(Aminooxyethyl)nucleoside amidites and 2′-O-(dimethylaminooxyethyl) nucleoside amidites  
     [0176] 2′-(Dimethylaminooxyethoxy)nucleoside amidites 2′-(Dimethylaminooxyethoxy)nucleoside amidites (also known in the art as 2′-O-(dimethylaminooxyethyl)nucleoside amidites) are prepared as described in the following paragraphs. Adenosine, cytidine and guanosine nucleoside amidites are prepared similarly to the thymidine (5-methyluridine) except the exocyclic amines are protected with a benzoyl moiety in the case of adenosine and cytidine and with isobutyryl in the case of guanosine.  
     [0177] 5′-O-tert-Butyldiphenylsilyl-O 2 -2′-anhydro-5-methyluridine  
     [0178] O 2 -2′-anhydro-5-methyluridine (Pro. Bio. Sint., Varese, Italy, 100.0 g, 0.416 mmol), dimethylaminopyridine (0.66 g, 0.013 eq, 0.0054 mmol) were dissolved in dry pyridine (500 ml) at ambient temperature under an argon atmosphere and with mechanical stirring. tert-Butyldiphenylchlorosilane (125.8 g, 119.0 mL, 1.1 eq, 0.458 mmol) was added in one portion. The reaction was stirred for 16 h at ambient temperature. TLC (R f  0.22, EtOAc) indicated a complete reaction. The solution was concentrated under reduced pressure to a thick oil. This was partitioned between CH 2 Cl 2  (1 L) and saturated sodium bicarbonate (2×1 L) and brine (1 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to a thick oil. The oil was dissolved in a 1:1 mixture of EtOAc and ethyl ether (600 mL) and cooling the solution to −10° C. afforded a white crystalline solid which was collected by filtration, washed with ethyl ether (3×2 00 mL) and dried (40° C., 1 mm Hg, 24 h) to afford 149 g of white solid (74.8%). TLC and NMR spectroscopy were consistent with pure product.  
     [0179] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine  
     [0180] In the fume hood, ethylene glycol (350 mL, excess) was added cautiously with manual stirring to a 2 L stainless steel pressure reactor containing borane in tetrahydrofuran (1.0 M, 2.0 eq, 622 mL). (Caution:evolves hydrogen gas). 5′-O-tert-Butyldiphenylsilyl-O 2 -2′-anhydro-5-methyluridine (149 g, 0.311 mol) and sodium bicarbonate (0.074 g, 0.003 eq) were added with manual stirring. The reactor was sealed and heated in an oil bath until an internal temperature of 160° C. was reached and then maintained for 16 h (pressure&lt;100 psig). The reaction vessel was cooled to ambient temperature and opened. TLC (EtOAc, R f  0.67 for desired product and R f  0.82 for ara-T side product) indicated about 70% conversion to the product. The solution was concentrated under reduced pressure (10 to 1 mm Hg) in a warm water bath (40-100° C.) with the more extreme conditions used to remove the ethylene glycol. (Alternatively, once the THF has evaporated the solution can be diluted with water and the product extracted into EtOAc). The residue was purified by column chromatography (2 kg silica gel, EtOAc-hexanes gradient 1:1 to 4:1). The appropriate fractions were combined, evaporated and dried to afford 84 g of a white crisp foam (50%), contaminated starting material (17.4 g, 12% recovery) and pure reusable starting material (20 g, 13% recovery). TLC and NMR spectroscopy were consistent with 99% pure product.  
     [0181] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine  
     [0182] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine (20 g, 36.98 mmol) was mixed with triphenylphosphine (11.63 g, 44.36 mmol) and N-hydroxyphthalimide (7.24g, 44.36mmol) and dried over P 2 O 5  under high vacuum for two days at 40° C. The reaction mixture was flushed with argon and dissolved in dry THF (369.8 mL, Aldrich, sure seal bottle). Diethyl-azodicarboxylate (6.98 mL, 44.36 mmol) was added dropwise to the reaction mixture with the rate of addition maintained such that the resulting deep red coloration is just discharged before adding the next drop. The reaction mixture was stirred for 4 hrs., after which time TLC (EtOAc:hexane, 60:40) indicated that the reaction was complete. The solvent was evaporated in vacuuo and the residue purified by flash column chromatography (eluted with 60:40 EtOAc:hexane), to yield 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine as white foam (21.819 g, 86%) upon rotary evaporation.  
     [0183] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine  
     [0184] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine (3.1 g, 4.5 mmol) was dissolved in dry CH 2 Cl 2  (4.5 mL) and methylhydrazine (30 mL, 4.64 mmol) was added dropwise at −10° C. to 0° C. After 1 h the mixture was filtered, the filtrate washed with ice cold CH 2 Cl 2 , and the combined organic phase was washed with water and brine and dried (anhydrous Na 2 SO 4 ). The solution was filtered and evaporated to afford 2′-O-(aminooxyethyl) thymidine, which was then dissolved in MeOH (67.5 mL). Formaldehyde (20% aqueous solution, w/w, 1.1 eq.) was added and the resulting mixture was stirred for 1 h. The solvent was removed under vacuum and the residue was purified by column chromatography to yield 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy) ethyl]-5-methyluridine as white foam (1.95 g, 78%) upon rotary evaporation.  
     [0185] 5′-O-tert-Butyldiphenylsilyl-2′-O-[N,N dimethylaminooxyethyl]-5-methyluridine  
     [0186] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine (1.77 g, 3.12 mmol) was dissolved in a solution of 1M pyridinium p-toluenesulfonate (PPTS) in dry MeOH (30.6 mL) and cooled to 10° C. under inert atmosphere. Sodium cyanoborohydride (0.39 g, 6.13 mmol) was added and the reaction mixture was stirred. After 10 minutes the reaction was warmed to room temperature and stirred for 2 h. while the progress of the reaction was monitored by TLC (5% MeOH in CH 2 Cl 2 ). Aqueous NaHCO 3  solution (5%, 10 mL) was added and the product was extracted with EtOAc (2×20 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness. This entire procedure was repeated with the resulting residue, with the exception that formaldehyde (20% w/w, 30 mL, 3.37 mol) was added upon dissolution of the residue in the PPTS/MeOH solution. After the extraction and evaporation, the residue was purified by flash column chromatography and (eluted with 5% MeOH in CH 2 Cl 2 ) to afford 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine as a white foam (14.6 g, 80%) upon rotary evaporation.  
     [0187] 2′-O-(dimethylaminooxyethyl)-5-methyluridine  
     [0188] Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and TEA (1.67 mL, 12 mmol, dry, stored over KOH) and added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol). The reaction was stirred at room temperature for 24 hrs and monitored by TLC (5% MeOH in CH 2 Cl 2 ). The solvent was removed under vacuum and the residue purified by flash column chromatography (eluted with 10% MeOH in CH 2 Cl 2 ) to afford 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%) upon rotary evaporation of the solvent.  
     [0189] 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine  
     [0190] 2′-O-(dimethylaminooxyethyl)-5-methyluridine (750 mg, 2.17 mmol) was dried over P 2 O 5  under high vacuum overnight at 40° C., co-evaporated with anhydrous pyridine (20 mL), and dissolved in pyridine (11 mL) under argon atmosphere. 4-dimethylaminopyridine (26.5 mg, 2.60 mmol) and 4,4′-dimethoxytrityl chloride (880 mg, 2.60 mmol) were added to the pyridine solution and the reaction mixture was stirred at room temperature until all of the starting material had reacted. Pyridine was removed under vacuum and the residue was purified by column chromatography (eluted with 10% MeOH in CH 2 Cl 2  containing a few drops of pyridine) to yield 5′-O-DMT-2′-O-(dimethylamino-oxyethyl)-5-methyluridine (1.13 g, 80%) upon rotary evaporation.  
     [0191] 5′-O-DMT-2′-O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] 
     [0192] 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine (1.08 g, 1.67 mmol) was co-evaporated with toluene (20 mL), N,N-diisopropylamine tetrazonide (0.29 g, 1.67 mmol) was added and the mixture was dried over P 2 O 5  under high vacuum overnight at 40° C. This was dissolved in anhydrous acetonitrile (8.4 mL) and 2-cyanoethyl-N,N,N 1 ,N 1 -tetraisopropylphosphoramidite (2.12 mL, 6.08 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 h under inert atmosphere. The progress of the reaction was monitored by TLC (hexane:EtOAc 1:1). The solvent was evaporated, then the residue was dissolved in EtOAc (70 mL) and washed with 5% aqueous NaHCO 3  (40 mL). The EtOAc layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue obtained was purified by column chromatography (EtOAc as eluent) to afford 5′-O-DMT-2′-O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] as a foam (1.04 g, 74.9%) upon rotary evaporation.  
     [0193] 2′-(Aminooxyethoxy)nucleoside amidites  
     [0194] 2′-(Aminooxyethoxy)nucleoside amidites (also known in the art as 2 1 -O-(aminooxyethyl)nucleoside amidites) are prepared as described in the following paragraphs. Adenosine, cytidine and thymidine nucleoside amidites are prepared similarly.  
     [0195] N2-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] 
     [0196] The 2′-O-aminooxyethyl guanosine analog may be obtained by selective 2′-O-alkylation of diaminopurine riboside. Multigram quantities of diaminopurine riboside may be purchased from Schering AG (Berlin) to provide 2′-O-(2-ethylacetyl) diaminopurine riboside along with a minor amount of the 3′-O-isomer. 2′-O-(2-ethylacetyl)diaminopurine riboside may be resolved and converted to 2′-O-(2-ethylacetyl)guanosine by treatment with adenosine deaminase. (McGee, D. P. C., Cook, P. D., Guinosso, C. J., WO 94/02501 A1 940203.) Standard protection procedures should afford 2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine and 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine which may be reduced to provide 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-hydroxyethyl)-5′-O-(4,4′-dimethoxytrityl)guanosine. As before the hydroxyl group may be displaced by N-hydroxyphthalimide via a Mitsunobu reaction, and the protected nucleoside may be phosphitylated as usual to yield 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-([2-phthalmidoxy]ethyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite].  
     [0197] 2′-dimethylaminoethoxyethoxy (2′-DHAEOE)nucleoside amidites  
     [0198] 2′-dimethylaminoethoxyethoxy nucleoside amidites (also known in the art as 2′-O-dimethylaminoethoxyethyl, i.e., 2′-O—CH 2 —O—CH 2 —N(CH 2 ) 2 , or 2′-DMAEOE nucleoside amidites) are prepared as follows. Other nucleoside amidites are prepared similarly.  
     [0199] 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl]-5-methyl uridine  
     [0200] 2[2-(Dimethylamino)ethoxy]ethanol (Aldrich, 6.66 g, 50 mmol) was slowly added to a solution of borane in tetra-hydrofuran (1 M, 10 mL, 10 mmol) with stirring in a 100 mL bomb. (Caution: Hydrogen gas evolves as the solid dissolves). O 2 —,2′-anhydro-5-methyluridine (1.2 g, 5 mmol), and sodium bicarbonate (2.5 mg) were added and the bomb was sealed, placed in an oil bath and heated to 155° C. for 26 h. then cooled to room temperature. The crude solution was concentrated, the residue was diluted with water (200 mL) and extracted with hexanes (200 mL). The product was extracted from the aqueous layer with EtOAc (3×200 mL) and the combined organic layers were washed once with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 5:100:2 MeOH/CH 2 Cl 2 /TEA) as the eluent. The appropriate fractions were combined and evaporated to afford the product as a white solid.  
     [0201] 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl)]-5-methyl uridine  
     [0202] To 0.5 g (1.3 mmol) of 2′-O-[2(2-N,N-dimethylamino-ethoxy)ethyl)]-5-methyl uridine in anhydrous pyridine (8 mL), was added TEA (0.36 mL) and dimethoxytrityl chloride (DMT-Cl, 0.87 g, 2 eq.) and the reaction was stirred for 1 h. The reaction mixture was poured into water (200 mL) and extracted with CH 2 Cl 2  (2×200 mL). The combined CH 2 Cl 2  layers were washed with saturated NaHCO 3  solution, followed by saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (eluted with 5:100:1 MeOH/CH 2 Cl 2 /TEA) to afford the product.  
     [0203] 5′-O-Dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine-3′-O-(cyanoethyl-N,N-diisopropyl)phosphoramidite  
     [0204] Diisopropylaminotetrazolide (0.6 g) and 2-cyanoethoxy-N,N-diisopropyl phosphoramidite (1.1 mL, 2 eq.) were added to a solution of 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl)]-5-methyluridine (2.17 g, 3 mmol) dissolved in CH 2 Cl 2  (20 mL) under an atmosphere of argon. The reaction mixture was stirred overnight and the solvent evaporated. The resulting residue was purified by silica gel column chromatography with EtOAc as the eluent to afford the title compound.  
     Example 2  
     [0205] Oligonucleotide Synthesis  
     [0206] Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.  
     [0207] Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation was effected by utilizing a 10% w/v solution of 3H-1,2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the oxidation of the phosphite linkages. The thiation reaction step time was increased to 180 sec and preceded by the normal capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55° C. (12-16 hr), the oligonucleotides were recovered by precipitating with &gt;3 volumes of ethanol from a 1 M NH 4 oAc solution. Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.  
     [0208] Alkyl phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 4,469,863, herein incorporated by reference.  
     [0209] 3′-Deoxy-3′-methylene phosphonate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050, herein incorporated by reference.  
     [0210] Phosphoramidite oligonucleotides are prepared as described in U.S. Pat. No., 5,256,775 or U.S. Pat. No. 5,366,878, herein incorporated by reference.  
     [0211] Alkylphosphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (published as WO 94/17093 and WO 94/02499, respectively), herein incorporated by reference.  
     [0212] 3′-Deoxy-3′-amino phosphoramidate oligonucleotides are prepared as described in U.S. Pat. No. 5,476,925, herein incorporated by reference.  
     [0213] Phosphotriester oligonucleotides are prepared as described in U.S. Pat. No. 5,023,243, herein incorporated by reference.  
     [0214] Borano phosphate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198, both herein incorporated by reference.  
     Example 3  
     [0215] Oligonucleoside Synthesis  
     [0216] Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethyl-hydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligonucleosides, also identified as amide-4 linked oligonucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and P⊚O or P═S linkages are prepared as described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference.  
     [0217] Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Pat. Nos 5,264,562 and 5,264,564, herein incorporated by reference.  
     [0218] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.  
     Example 4  
     [0219] PNA Synthesis  
     [0220] Peptide nucleic acids (PNAs) are prepared in accordance with any of the various procedures referred to in Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications,  Bioorganic &amp; Medicinal Chemistry,  1996, 4, 5-23. They may also be prepared in accordance with U.S. Pat. Nos. 5,539,082, 5,700,922, and 5,719,262, herein incorporated by reference.  
     Example 5  
     [0221] Synthesis of Chimeric Oligonucleotides  
     [0222] Chimeric oligonucleotides, oligonucleosides or mixed oligonucleotides/oligonucleosides of the invention can be of several different types. These include a first type wherein the “gap” segment of linked nucleosides is positioned between 5′ and 3′ “wing” segments of linked nucleosides and a second “open end” type wherein the “gap” segment is located at either the 3′ or the 5′ terminus of the oligomeric compound. Oligonucleotides of the first type are also known in the art as “gapmers” or gapped oligonucleotides. Oligonucleotides of the second type are also known in the art as “hemimers” or “wingmers”.  
     [0223] [2′-O—Me]-[2′-deoxy]-[2′-O—Me]Chimeric Phosphorothioate Oligonucleotides  
     [0224] Chimeric oligonucleotides having 2′-O-alkyl phosphorothioate and 2′-deoxy phosphorothioate oligonucleotide segments are synthesized using an Applied Biosystems automated DNA synthesizer Model 394, as above. Oligonucleotides are synthesized using the automated synthesizer and 2′-deoxy-5′-dimethoxytrityl-3′-O-phosphor-amidite for the DNA portion and 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite for 5′ and 3′ wings. The standard synthesis cycle is modified by incorporating coupling steps with increased reaction times for the 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite. The fully protected oligonucleotide is cleaved from the support and deprotected in concentrated ammonia (NH 4 OH) for 12-16 hr at 55° C. The deprotected oligo is then recovered by an appropriate method (precipitation, column chromatography, volume reduced in vacuo and analyzed spetrophotometrically for yield and for purity by capillary electrophoresis and by mass spectrometry.  
     [0225] [2′-O-(2-Methoxyethyl)]-[2′-deoxy]-[2′-O-(Methoxyethyl)]Chimeric Phosphorothioate Oligonucleotides  
     [0226] [2′-O-(2-methoxyethyl)]-[2′-deoxy]-[-2′-O-(methoxyethyl)]chimeric phosphorothioate oligonucleotides were prepared as per the procedure above for the 2′-O-methyl chimeric oligonucleotide, with the substitution of 2′-O-(methoxyethyl)amidites for the 2′-O-methyl amidites.  
     [0227] [2′-O-(2-Methoxyethyl)Phosphodiester]-[2′-deoxy Phosphorothioate]-[2′-O-(2-Methoxyethyl)Phosphodiester]Chimeric Oligonucleotides  
     [0228] [2′-O-(2-methoxyethyl phosphodiester]-[2′-deoxy phosphorothioate]-[2′-O-(methoxyethyl)phosphodiester]chimeric oligonucleotides are prepared as per the above procedure for the 2′-O-methyl chimeric oligonucleotide with the substitution of 2′-O-(methoxyethyl)amidites for the 2′-O-methyl amidites, oxidation with iodine to generate the phosphodiester internucleotide linkages within the wing portions of the chimeric structures and sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) to generate the phosphorothioate internucleotide linkages for the center gap.  
     [0229] Other chimeric oligonucleotides, chimeric oligonucleosides and mixed chimeric oligonucleotides/oligonucleosides are synthesized according to U.S. Pat. No. 5,623,065, herein incorporated by reference.  
     Example 6  
     [0230] Oligonucleotide Isolation  
     [0231] After cleavage from the controlled pore glass solid support and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligonucleotides or oligonucleosides are recovered by precipitation out of 1 M NH 4 OAc with &gt;3 volumes of ethanol. Synthesized oligonucleotides were analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis and judged to be at least 70% full length material. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis was determined by the ratio of correct molecular weight relative to the −16 amu product (±32 ±48). For some studies oligonucleotides were purified by HPLC, as described by Chiang et al.,  J. Biol. Chem.  1991, 266, 18162-18171. Results obtained with HPLC-purified material were similar to those obtained with non-HPLC purified material.  
     Example 7  
     [0232] Oligonucleotide Synthesis—96 Well Plate Format  
     [0233] Oligonucleotides were synthesized via solid phase P(III) phosphoramidite chemistry on an automated synthesizer capable of assembling 96 sequences simultaneously in a 96-well format. Phosphodiester internucleotide linkages were afforded by oxidation with aqueous iodine. Phosphorothioate internucleotide linkages were generated by sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) in anhydrous acetonitrile. Standard base-protected beta-cyanoethyl-diiso-propyl phosphoramidites were purchased from commercial vendors (e.g. PE-Applied Biosystems, Foster City, Calif., or Pharmacia, Piscataway, N.J.). Non-standard nucleosides are synthesized as per standard or patented methods. They are utilized as base protected beta-cyanoethyldiisopropyl phosphoramidites.  
     [0234] Oligonucleotides were cleaved from support and deprotected with concentrated NH 4 OH at elevated temperature (55-60° C.) for 12-16 hours and the released product then dried in vacuo. The dried product was then re-suspended in sterile water to afford a master plate from which all analytical and test plate samples are then diluted utilizing robotic pipettors.  
     Example 8  
     [0235] Oligonucleotide Analysis—96-Well Plate Format  
     [0236] The concentration of oligonucleotide in each well was assessed by dilution of samples and UV absorption spectroscopy. The full-length integrity of the individual products was evaluated by capillary electrophoresis (CE) in either the 96-well format (Beckman P/ACE™ MDQ) or, for individually prepared samples, on a commercial CE apparatus (e.g., Beckman P/ACE™ 5000, ABI 270). Base and backbone composition was confirmed by mass analysis of the compounds utilizing electrospray-mass spectroscopy. All assay test plates were diluted from the master plate using single and multi-channel robotic pipettors. Plates were judged to be acceptable if at least 85% of the compounds on the plate were at least 85% full length.  
     Example 9  
     [0237] Cell Culture and Oligonucleotide Treatment  
     [0238] The effect of antisense compounds on target nucleic acid expression can be tested in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. This can be routinely determined using, for example, PCR or Northern blot analysis. The following cell types are provided for illustrative purposes, but other cell types can be routinely used, provided that the target is expressed in the cell type chosen. This can be readily determined by methods routine in the art, for example Northern blot analysis, ribonuclease protection assays, or RT-PCR.  
     [0239] T-24 Cells:  
     [0240] The human transitional cell bladder carcinoma cell line T-24 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). T-24 cells were routinely cultured in complete McCoy&#39;s 5A basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence. Cells were seeded into 96-well plates (Falcon-Primaria #3872) at a density of 7000 cells/well for use in RT-PCR analysis.  
     [0241] For Northern blotting or other analysis, cells may be seeded onto 100 mm or other standard tissue culture plates and treated similarly, using appropriate volumes of medium and oligonucleotide.  
     [0242] A549 Cells:  
     [0243] The human lung carcinoma cell line A549 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). A549 cells were routinely cultured in DMEM basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence.  
     [0244] NHDF Cells:  
     [0245] Human neonatal dermal fibroblast (NHDF) were obtained from the Clonetics Corporation (Walkersville, Md.). NHDFs were routinely maintained in Fibroblast Growth Medium (Clonetics Corporation, Walkersville, Md.) supplemented as recommended by the supplier. Cells were maintained for up to 10 passages as recommended by the supplier.  
     [0246] HEK Cells:  
     [0247] Human embryonic keratinocytes (HEK) were obtained from the Clonetics Corporation (Walkersville, Md.). HEKs were routinely maintained in Keratinocyte Growth Medium (Clonetics Corporation, Walkersville, Md.) formulated as recommended by the supplier. Cells were routinely maintained for up to 10 passages as recommended by the supplier.  
     [0248] Treatment with Antisense Compounds:  
     [0249] When cells reached 70% confluency, they were treated with oligonucleotide. For cells grown in 96-well plates, wells were washed once with 100 μL OPTI-MEM™-1 reduced-serum medium (Invitrogen Corporation, Carlsbad, Calif.) and then treated with 130 μL of OPTI-MEM™-1 containing 3.75 μg/mL LIPOFECTIN™ (Invitrogen Corporation, Carlsbad, Calif.) and the desired concentration of oligonucleotide. After 4-7 hours of treatment, the medium was replaced with fresh medium. Cells were harvested 16-24 hours after oligonucleotide treatment.  
     [0250] The concentration of oligonucleotide used varies from cell line to cell line. To determine the optimal oligonucleotide concentration for a particular cell line, the cells are treated with a positive control oligonucleotide at a range of concentrations. For human cells the positive control oligonucleotide is selected from either ISIS 13920 (TCCGTCATCGCTCCTCAGGG, SEQ ID NO: 1) which is targeted to human H-ras, or ISIS 18078, (GTGCGCGCGAGCCCGAAATC, SEQ ID NO: 2) which is targeted to human Jun-N-terminal kinase-2 (JNK2). Both controls are 2′-O-methoxyethyl gapmers (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone. For mouse or rat cells the positive control oligonucleotide is ISIS 15770, ATGCATTCTGCCCCCAAGGA, SEQ ID NO: 3, a 2′-O-methoxyethyl gapmer (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone which is targeted to both mouse and rat c-raf. The concentration of positive control oligonucleotide that results in 80% inhibition of c-Ha-ras (for ISIS 13920) or c-raf (for ISIS 15770) mRNA is then utilized as the screening concentration for new oligonucleotides in subsequent experiments for that cell line. If 80% inhibition is not achieved, the lowest concentration of positive control oligonucleotide that results in 60% inhibition of H-ras or c-raf mRNA is then utilized as the oligonucleotide screening concentration in subsequent experiments for that cell line. If 60% inhibition is not achieved, that particular cell line is deemed as unsuitable for oligonucleotide transfection experiments. The concentrations of antisense oligonucleotides used herein are from 50 nM to 300 nM.  
     Example 10  
     [0251] Analysis of Oligonucleotide Inhibition of Hypothetical Tumor Endothelial Marker Expression  
     [0252] Antisense modulation of hypothetical tumor endothelial marker expression can be assayed in a variety of ways known in the art. For example, hypothetical tumor endothelial marker mRNA levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or real-time PCR (RT-PCR). Real-time quantitative PCR is presently preferred. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. The preferred method of RNA analysis of the present invention is the use of total cellular RNA as described in other examples herein. Methods of RNA isolation are taught in, for example, Ausubel, F. M. et al.,  Current Protocols in Molecular Biology,  Volume 1, pp. 4.1.1-4.2.9 and 4.5.1-4.5.3, John Wiley &amp; Sons, Inc., 1993. Northern blot analysis is routine in the art and is taught in, for example, Ausubel, F. M. et al.,  Current Protocols in Molecular Biology,  Volume 1, pp. 4.2.1-4.2.9, John Wiley &amp; Sons, Inc., 1996. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available ABI PRISM™ 7700 Sequence Detection System, available from PE-Applied Biosystems, Foster City, Calif. and used according to manufacturer&#39;s instructions.  
     [0253] Protein levels of hypothetical tumor endothelial marker can be quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), ELISA or fluorescence-activated cell sorting (FACS). Antibodies directed to hypothetical tumor endothelial marker can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, Mich.), or can be prepared via conventional antibody generation methods. Methods for preparation of polyclonal antisera are taught in, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 11.12.1-11.12.9, John Wiley &amp; Sons, Inc., 1997). Preparation of monoclonal antibodies is taught in, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 11.4.1-11.11.5, John Wiley &amp; Sons, Inc., 1997).  
     [0254] Immunoprecipitation methods are standard in the art and can be found at, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 10.16.1-10.16.11, John Wiley &amp; Sons, Inc., 1998). Western blot (immunoblot) analysis is standard in the art and can be found at, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 10.8.1-10.8.21, John Wiley &amp; Sons, Inc., 1997). Enzyme-linked immunosorbent assays (ELISA) are standard in the art and can be found at, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 11.2.1-11.2.22, John Wiley &amp; Sons, Inc., 1991).  
     Example 11  
     [0255] Poly(A)+ mRNA Isolation  
     [0256] Poly(A)+ mRNA was isolated according to Miura et al., ( Clin. Chem.,  1996, 42, 1758-1764). Other methods for poly(A)+ mRNA isolation are taught in, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 1, pp. 4.5.1-4.5.3, John Wiley &amp; Sons, Inc., 1993). Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 60 μL lysis buffer (10 mM Tris-HCl, pH 7.6, 1 mM EDTA, 0.5 M NaCl, 0.5% NP-40, 20 mM vanadyl-ribonucleoside complex) was added to each well, the plate was gently agitated and then incubated at room temperature for five minutes. 55 μL of lysate was transferred to Oligo d(T) coated 96-well plates (AGCT Inc., Irvine Calif.). Plates were incubated for 60 minutes at room temperature, washed 3 times with 200 μL of wash buffer (10 mM Tris-HCl pH 7.6, 1 mM EDTA, 0.3 M NaCl). After the final wash, the plate was blotted on paper towels to remove excess wash buffer and then air-dried for 5 minutes. 60 μL of elution buffer (5 mM Tris-HCl pH 7.6), preheated to 70° C., was added to each well, the plate was incubated on a 90° C. hot plate for 5 minutes, and the eluate was then transferred to a fresh 96-well plate.  
     [0257] Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions.  
     Example 12  
     [0258] Total RNA Isolation  
     [0259] Total RNA was isolated using an RNEASY 96™ kit and buffers purchased from Qiagen Inc. (Valencia, Calif.) following the manufacturer&#39;s recommended procedures. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 150 μL Buffer RLT was added to each well and the plate vigorously agitated for 20 seconds. 150 μL of 70% ethanol was then added to each well and the contents mixed by pipetting three times up and down. The samples were then transferred to the RNEASY 96™ well plate attached to a QIAVAC™ manifold fitted with a waste collection tray and attached to a vacuum source. Vacuum was applied for 1 minute. 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and incubated for 15 minutes and the vacuum was again applied for 1 minute. An additional 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and the vacuum was applied for 2 minutes. 1 mL of Buffer RPE was then added to each well of the RNEASY 96™ plate and the vacuum applied for a period of 90 seconds. The Buffer RPE wash was then repeated and the vacuum was applied for an additional 3 minutes. The plate was then removed from the QIAVAC™ manifold and blotted dry on paper towels. The plate was then re-attached to the QIAVAC™ manifold fitted with a collection tube rack containing 1.2 mL collection tubes. RNA was then eluted by pipetting 170 μL water into each well, incubating 1 minute, and then applying the vacuum for 3 minutes.  
     [0260] The repetitive pipetting and elution steps may be automated using a QIAGEN Bio-Robot 9604 (Qiagen, Inc., Valencia Calif.). Essentially, after lysing of the cells on the culture plate, the plate is transferred to the robot deck where the pipetting, DNase treatment and elution steps are carried out.  
     Example 13  
     [0261] Real-time Quantitative PCR Analysis of Hypothetical Tumor Endothelial Marker mRNA Levels  
     [0262] Quantitation of hypothetical tumor endothelial marker mRNA levels was determined by real-time quantitative PCR using the ABI PRISM™ 7700 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer&#39;s instructions. This is a closed-tube, non-gel-based, fluorescence detection system which allows high-throughput quantitation of polymerase chain reaction (PCR) products in real-time. As opposed to standard PCR in which amplification products are quantitated after the PCR is completed, products in real-time quantitative PCR are quantitated as they accumulate. This is accomplished by including in the PCR reaction an oligonucleotide probe that anneals specifically between the forward and reverse PCR primers, and contains two fluorescent dyes. A reporter dye (e.g., FAM or JOE, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 5′ end of the probe and a quencher dye (e.g., TAMRA, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 3′ end of the probe. When the probe and dyes are intact, reporter dye emission is quenched by the proximity of the 3′ quencher dye. During amplification, annealing of the probe to the target sequence creates a substrate that can be cleaved by the 5′-exonuclease activity of Taq polymerase. During the extension phase of the PCR amplification cycle, cleavage of the probe by Taq polymerase releases the reporter dye from the remainder of the probe (and hence from the quencher moiety) and a sequence-specific fluorescent signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored at regular intervals by laser optics built into the ABI PRISMS 7700 Sequence Detection System. In each assay, a series of parallel reactions containing serial dilutions of mRNA from untreated control samples generates a standard curve that is used to quantitate the percent inhibition after antisense oligonucleotide treatment of test samples.  
     [0263] Prior to quantitative PCR analysis, primer-probe sets specific to the target gene being measured are evaluated for their ability to be “multiplexed” with a GAPDH amplification reaction. In multiplexing, both the target gene and the internal standard gene GAPDH are amplified concurrently in a single sample. In this analysis, mRNA isolated from untreated cells is serially diluted. Each dilution is amplified in the presence of primer-probe sets specific for GAPDH only, target gene only (“single-plexing”), or both (multiplexing). Following PCR amplification, standard curves of GAPDH and target mRNA signal as a function of dilution are generated from both the single-plexed and multiplexed samples. If both the slope and correlation coefficient of the GAPDH and target signals generated from the multiplexed samples fall within 10% of their corresponding values generated from the single-plexed samples, the primer-probe set specific for that target is deemed multiplexable. Other methods of PCR are also known in the art.  
     [0264] PCR reagents were obtained from Invitrogen Corporation, (Carlsbad, Calif.). RT-PCR reactions were carried out by adding 20 μL PCR cocktail (2.5×PCR buffer (—MgCl 2 ), 6.6 mM MgCl 2 , 375 , each of DATP, dCTP, dCTP and dGTP, 375 nM each of forward primer and reverse primer, 125 nM of probe, 4 Units RNAse inhibitor, 1.25 Units PLATINUM® Taq, 5 Units MuLV reverse transcriptase, and 2.5×ROX dye) to 96-well plates containing 30 μL total RNA solution. The RT reaction was carried out by incubation for 30 minutes at 48° C. Following a 10 minute incubation at 95° C. to activate the PLATINUM® Taq, 40 cycles of a two-step PCR protocol were carried out: 95° C. for 15 seconds (denaturation) followed by 60° C. for 1.5 minutes (annealing/extension).  
     [0265] Gene target quantities obtained by real time RT-PCR are normalized using either the expression level of GAPDH, a gene whose expression is constant, or by quantifying total RNA using RiboGreen™ (Molecular Probes, Inc. Eugene, Or.). GAPDH expression is quantified by real time RT-PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RiboGreen™ RNA quantification reagent from Molecular Probes. Methods of RNA quantification by RiboGreen™ are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374).  
     [0266] In this assay, 170 μL of RiboGreen™ working reagent (RiboGreen™ reagent diluted 1:350 in 10 mM Tris-HCl, 1 mM EDTA, pH 7.5) is pipetted into a 96-well plate containing 30 μL purified, cellular RNA. The plate is read in a CytoFluor 4000 (PE Applied Biosystems) with excitation at 480 nm and emission at 520 nm.  
     [0267] Probes and primers to human hypothetical tumor endothelial marker were designed to hybridize to a human hypothetical tumor endothelial marker sequence, using published sequence information (GenBank accession number AB062750.1, incorporated herein as SEQ ID NO: 4). For human hypothetical tumor endothelial marker the PCR primers were: forward primer: CTGGGCCACATCAGAATAAGG (SEQ ID NO: 5) reverse primer: CGCAATCAGGACAGTCAGCAT (SEQ ID NO: 6) and the PCR probe was: FAM-CTTGGCCCCATCCTCTCACAGCCTAG-TAMRA (SEQ ID NO: 7) where FAM is the fluorescent dye and TAMRA is the quencher dye. For human GAPDH the PCR primers were: forward primer: GAAGGTGAAGGTCGGAGTC(SEQ ID NO: 8) reverse primer: GAAGATGGTGATGGGATTTC (SEQ ID NO: 9) and the PCR probe was: 5′ JOE-CAAGCTTCCCGTTCTCAGCC-TAMRA 3′ (SEQ ID NO: 10) where JOE is the fluorescent reporter dye and TAMRA is the quencher dye.  
     Example 14  
     [0268] Northern Blot Analysis of Hypothetical Tumor Endothelial Marker mRNA Levels  
     [0269] Eighteen hours after antisense treatment, cell monolayers were washed twice with cold PBS and lysed in 1 mL RNAZOL™ (TEL-TEST “B” Inc., Friendswood, Tex.). Total RNA was prepared following manufacturer&#39;s recommended protocols. Twenty micrograms of total RNA was fractionated by electrophoresis through 1.2% agarose gels containing 1.1% formaldehyde using a MOPS buffer system (AMRESCO, Inc. Solon, Ohio). RNA was transferred from the gel to HYBOND™-N+ nylon membranes (Amersham Pharmacia Biotech, Piscataway, N.J.) by overnight capillary transfer using a Northern/Southern Transfer buffer system (TEL-TEST “B” Inc., Friendswood, Tex.). RNA transfer was confirmed by UV visualization. Membranes were fixed by UV cross-linking using a STRATALINKER™ UV Crosslinker 2400 (Stratagene, Inc, La Jolla, Calif.) and then probed using QUICKHYB™ hybridization solution (Stratagene, La Jolla, Calif.) using manufacturer&#39;s recommendations for stringent conditions.  
     [0270] To detect human hypothetical tumor endothelial marker, a human hypothetical tumor endothelial marker specific probe was prepared by PCR using the forward primer CTGGGCCACATCAGAATAAGG (SEQ ID NO: 5) and the reverse primer CGCAATCAGGACAGTCAGCAT (SEQ ID NO: 6). To normalize for variations in loading and transfer efficiency membranes were stripped and probed for human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RNA (Clontech, Palo Alto, Calif.).  
     [0271] Hybridized membranes were visualized and quantitated using a PHOSPHORIMAGER™ and IMAGEQUANT™ Software V3.3 (Molecular Dynamics, Sunnyvale, Calif.). Data was normalized to GAPDH levels in untreated controls.  
     Example 15  
     [0272] Antisense Inhibition of Human Hypothetical Tumor Endothelial Marker Expression by Chimeric Phosphorothioate Oligonucleotides Having 2′-MOE Wings and a Deoxy Gap  
     [0273] In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human hypothetical tumor endothelial marker RNA, using published sequences (GenBank accession number AB062750.1, incorporated herein as SEQ ID NO: 4, and the complement of residues 10000-105000 of GenBank accession number AC073341.9, representing a genomic sequence of hypothetical tumor endothelial marker, incorporated herein as SEQ ID NO: 11). The oligonucleotides are shown in Table 1. “Target site” indicates the first (5′-most)nucleotide number on the particular target sequence to which the oligonucleotide binds. All compounds in Table 1 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of ten 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′directions) by five-nucleotide “wings”. The wings are composed of 2′-methoxyethyl (2′-MOE)nucleotides. The internucleoside (backbone) linkages are phosphorothioate (P═S) throughout the oligonucleotide. All cytidine residues are 5-methylcytidines. The compounds were analyzed for their effect on human hypothetical tumor endothelial marker mRNA levels by quantitative real-time PCR as described in other examples herein. Data are averages from two experiments in which A549 cells were treated with the oligonucleotides of the present invention. The positive control for each datapoint is identified in the table by sequence ID number. If present, “N.D.” indicates “no data”.  
                   TABLE 1                          Inhibition of human hypothetical tumor endothelial marker           mRNA levels by chimeric phosphorothioate oligonucleotides       having 2′-MOE wings and a deoxy gap                                                         TARGET                   CONTROL                   SEQ ID   TARGET           SEQ ID   SEQ ID       ISIS #   REGION   NO   SITE   SEQUENCE   % INHIB   NO   NO                                                         208361   5′UTR   4   63   tcagcttcctgagtctcccg   90   12   1                   208362   5′UTR   4   89   agcatcgttgtcgtactgcc   81   13   1               208363   5′UTR   4   122   ccatgcacatttggagaagg   89   14   1               208364   5′UTR   4   129   cctttccccatgcacatttg   58   15   1               208365   Start   4   198   gggtcatcgtctctttgacg   56   16   1           Codon               208366   Coding   4   242   taaaattctgccatcgataa   83   17   1               208367   Coding   4   292   tctggagacacaggaaatgc   47   18   1               208368   Coding   4   313   gctgttttcacatacggtgt   34   19   1               208369   Coding   4   403   gggcagcttcgtggttcacg   80   20   1               208370   Coding   4   465   gcatcgtggatttgggtccg   80   21   1               208371   Coding   4   505   gcctgctgaaaggagggcgt   44   22   1               208372   Coding   4   531   tggaaatggtgcaggaagaa   79   23   1               208373   Coding   4   680   gtccttcctggtaccggaga   80   24   1               208374   Coding   4   747   gggacagctcatggctgtgg   83   25   1               208375   Coding   4   859   agcaaggcccccaggtcctc   79   26   1               208376   Coding   4   938   ggacaggaagccattgtcgg   51   27   1               208377   Coding   4   979   tggtggctgctgtgtccagg   94   28   1               208378   Coding   4   1114   ctgtgcgggctggagaagcc   68   29   1               208379   Coding   4   1182   Aggccgcttctgaagccttg   80   30   1               208380   Coding   4   1291   atggcgatggcttgttctct   46   31   1               208381   Coding   4   1437   cgagttcattggccaaatct   83   32   1               208382   Coding   4   1504   tatggttcattcgagcaccc   69   33   1               208383   Coding   4   1562   cggcaaggccaagggcgtga   88   34   1               208384   Coding   4   1597   tccaatggatctctctctgg   81   35   1               208385   Coding   4   1697   ctccacagagttcaagtacc   76   36   1               208386   Coding   4   1746   tgatgctcagggccttctgg   89   37   1               208387   Coding   4   1857   ggtaatgcctccggaagaag   60   38   1               208388   Coding   4   1917   catctttgatccacttcctg   36   39   1               208389   Coding   4   2021   actggcaggctgctcagggt   93   40   1               208390   Stop   4   2083   gggagttctcagaccttctt   69   41   1           Codon               208391   3′UTR   4   2132   acggctgtctccagggcttc   94   42   1               208392   3′UTR   4   2281   tgtcagataagtcactttca   87   43   1               208393   3′UTR   4   2318   gcttcttctacccaaaaagc   73   44   1               208394   3′UTR   4   2477   atggcagtcactcggcacct   92   45   1               208395   3′UTR   4   2518   gggtgcagctggacagaagc   83   46   1               208396   3′UTR   4   2588   tacgcccccttctcagtttc   78   47   1               208397   3′UTR   4   2619   gggcctgacttgcacaaacc   90   48   1               208398   3′UTR   4   2704   ctaacgtggccaattcttcc   88   49   1               208399   3′UTR   4   2745   gaggcacagagcactcacca   89   50   1               208400   3′UTR   4   2940   aggctgcagcatttgacact   82   51   1               208401   3′UTR   4   2990   cctgcggtgoatcctacata   96   52   1               208402   3′UTR   4   3025   cacagtccactgcacactct   56   53   1               208403   3′UTR   4   3096   caatgagtaaaacatcaggg   80   54   1               208404   3′UTR   4   3109   gggaaaaacattccaatgag   72   55   1               208405   3′UTR   4   3211   gaagatgatcgaaaagccca   77   56   1               208406   3′UTR   4   3309   ccacacatggtccccagcag   90   57   1               208407   3′UTR   4   3385   cactcaaaaacagcttgtca   81   58   1               208408   3′UTR   4   3507   gtcacaaattcccccaaacc   62   59   1               208409   3′UTR   4   3613   caggacagtcagcatgcctg   79   60   1               208410   3′UTR   4   3738   cagagttcacaaagcacatt   56   61   1               208411   3′UTR   4   3803   cactgtgatttggctgcttc   92   62   1               208412   3′UTR   4   3875   aagtggaatggtccacctgc   83   63   1               208413   3′UTR   4   4011   atgaggatctgctgaaaatg   71   64   1               208414   3′UTR   4   4054   ccgagatgctagaggcctct   89   65   1               208415   3′UTR   4   4219   gctctgacttctaaatgagc   85   66   1               208416   3′UTR   4   4256   tggcaggctgcgtttctcaa   93   67   1               208417   3′UTR   4   4262   attccctggcaggctgcgtt   96   68   1               208418   3′UTR   4   4347   Tcaaaaagcacgtttgcagg   89   69   1               208419   3′UTR   4   4427   ggagctatctgcttggagca   86   70   1               208420   3′UTR   4   4621   acgttccttttcctgtggcc   93   71   1               208421   3′UTR   4   4685   tgaactctccgcatttactc   50   72   1               208422   3′UTR   4   4715   ctggctataacatgcgttgg   84   73   1               208423   3′UTR   4   4756   aatacaacaatacgttcttt   43   74   1               208424   3′UTR   4   4780   atggctatagcttaacactg   85   75   1               208425   3′UTR   4   4795   acagtgacttttaacatggc   89   76   1               208426   3′UTR   4   4808   tgagaataaatgcacagtga   83   77   1               208427   3′UTR   4   4884   atatattctttacagtatca   88   78   1               208428   3′UTR   4   4911   tttatagaacattcatttac   3   79   1               208429   3′UTR   4   4965   atactctgaatagagatgat   74   80   1               208430   3′UTR   4   4984   ccaagttcataattttatta   25   81   1               208431   Intron   11   1442   ccttcagccccactgaagta   81   82   1               208432   Exon:   11   24455   tcattcttaccatacggtgt   38   83   1           Intron           Junction               208433   Exon:   11   24624   gatttcttaccacgtcctcc   47   84   1           Intron           Junction               208434   Intron   11   40376   tgctgaaaaactcctataca   69   85   1               208435   Intron   11   60232   ctttcactgcctgatgccca   86   86   1               208436   Intron   11   61676   actaatgatgttgaacatct   75   87   1               208437   Intron:   11   89188   Tttgatccaccttgcaaatt   53   88   1           Exon           Junction               208438   Intron:   11   91158   tccaaagactctgccaaagg   66   89   1           Exon           Junction                  
 
     [0274] As shown in Table 1, SEQ ID NOs 12, 13, 14, 17, 20, 21, 23, 24, 25, 26, 28, 29, 30, 32, 33, 34, 35, 36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 75, 76, 77, 78, 80, 82, 85, 86, 87 and 89 demonstrated at least 62% inhibition of human hypothetical tumor endothelial marker expression in this assay and are therefore preferred. The target sites to which these preferred sequences are complementary are herein referred to as “preferred target regions” and are therefore preferred sites for targeting by compounds of the present invention. These preferred target regions are shown in Table 2. The sequences represent the reverse complement of the preferred antisense compounds shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number of the corresponding target nucleic acid. Also shown in Table 2 is the species in which each of the preferred target regions was found.  
                   TABLE 2                          Sequence and position of preferred target regions identified           in hypothetical tumor endothelial marker.                                                 TARGET   TARGET       REV COMP       SEQ ID           SITEID   SEQ ID NO   SITE   SEQUENCE   OF SEQ ID   ACTIVE IN   NO                                                     125975   4   63   cgggagactcaggaagctga   12     H. sapiens     90                   125976   4   89   ggcagtacgacaacgatgct   13     H. sapiens     91               125977   4   122   ccttctceaaatgtgcatgg   14     H. sapiens     92               125980   4   242   ttatcgatggcagaatttta   17     H. sapiens     93               125983   4   403   cgtgaaccacgaagctgccc   20     H. sapiens     94               125984   4   465   cggacccaaatccacgatgc   21     H. sapiens     95               125986   4   531   ttcttcctgcaccatttcca   23     H. sapiens     96               125987   4   680   tctccggtaccaggaaggac   24     H. sapiens     97               125988   4   747   ccacagccatgagctgtccc   25     H. sapiens     98               125989   4   859   gaggacctgggggccttgct   26     H. sapiens     99               125991   4   979   cctggacacagcagccacca   28     H. sapiens     100               125992   4   1114   ggcttctccagcccgcacag   29     H. sapiens     101               125993   4   1182   caaggcttcagaagcggcct   30     H. sapiens     102               125995   4   1437   agatttggccaatgaactcg   32     H. sapiens     103               125996   4   1504   gggtgctcgaatgaaccata   33     H. sapiens     104               125997   4   1562   tcacgcccttggccttgccg   34     H. sapiens     105               125998   4   1597   ccagagagagatccattgga   35     H. sapiens     106               125999   4   1697   ggtacttgaactctgtggag   36     H. sapiens     107               126000   4   1746   ccagaaggccctgagcatca   37     H. sapiens     108               126003   4   2021   accctgagcagcctgccagt   40     H. sapiens     109               126004   4   2083   aagaaggtctgagaactccc   41     H. sapiens     110               126005   4   2132   gaagccctggagacagccgt   42     H. sapiens     111               126006   4   2281   tgaaagtgacttatctgaca   43     H. sapiens     112               126007   4   2318   gctttttgggtagaagaagc   44     H. sapiens     113               126008   4   2477   aggtgccgagtgactgccat   45     H. sapiens     114               126009   4   2518   gcttctgtccagctgcaccc   46     H. sapiens     115               126010   4   2588   gaaactgagaagggggcgta   47     H. sapiens     116               126011   4   2619   ggtttgtgcaagtcaggccc   48     H. sapiens     117               126012   4   2704   ggaagaattggccacgttag   49     H. sapiens     118               126013   4   2745   tggtgagtgctctgtgcctc   50     H. sapiens     119               126014   4   2940   agtgtcaaatgctgcagcct   51     H. sapiens     120               126015   4   2990   tatgtaggatgcaccgcagg   52     H. sapiens     121               126017   4   3096   ccctgatgttttactcattg   54     H. sapiens     122               126018   4   3109   ctcattggaatgtttttccc   55     H. sapiens     123               126019   4   3211   tgggcttttcgatcatcttc   56     H. sapiens     124               126020   4   3309   ctgctggggaccatgtgtgg   57     H. sapiens     125               126021   4   3385   tgacaagctgtttttgagtg   58     H. sapiens     126               126022   4   3507   ggtttgggggaatttgtgac   59     H. sapiens     127               126023   4   3613   caggcatgctgactgtcctg   60     H. sapiens     128               126025   4   3803   gaagcagccaaatcacagtg   62     H. sapiens     129               126026   4   3875   gcaggtggaccattccactt   63     H. sapiens     130               126027   4   4011   cattttcagcagatcctcat   64     H. sapiens     131               126028   4   4054   agaggcctctagcatctcgg   65     H. sapiens     132               126029   4   4219   gctcatttagaagtcagagc   66     H. sapiens     133               126030   4   4256   ttgagaaacgcagcctgcca   67     H. sapiens     134               126031   4   4262   aacgcagcctgccagggaat   68     H. sapiens     135               126032   4   4347   cctgcaaacgtgctttttga   69     H. sapiens     136               126033   4   4427   tgctccaagcagatagctcc   70     H. sapiens     137               126034   4   4621   ggccacaggaaaaggaacgt   71     H. sapiens     138               126036   4   4715   ccaacgcatgttatagccag   73     H. sapiens     139               126038   4   780   cagtgttaagctatagccat   75     H. sapiens     140               126039   4   4795   gccatgttaaaagtcactgt   76     H. sapiens     141               126040   4   4808   tcactgtgcatttattctca   77     H. sapiens     142               126041   4   4884   tgatactgtaaagaatatat   78     H. sapiens     143               126043   4   4965   atcatctctattcagagtat   80     H. sapiens     144               126045   11   1442   tacttcagtggggctgaagg   82     H. sapiens     145               126048   11   40376   tgtataggagtttttcagca   85     H. sapiens     146               126049   11   60232   tgggcatcaggcagtgaaag   86     H. sapiens     147               126050   11   61676   agatgttcaacatcattagt   87     H. sapiens     148               126052   11   91158   cctttggcagagtctttgga   89     H. sapiens     149                  
 
     [0275] As these “preferred target regions” have been found by experimentation to be open to, and accessible for, hybridization with the antisense compounds of the present invention, one of skill in the art will recognize or be able to ascertain, using no more than routine experimentation, further embodiments of the invention that encompass other compounds that specifically hybridize to these sites and consequently inhibit the expression of hypothetical tumor endothelial marker.  
     [0276] In one embodiment, the “preferred target region” may be employed in screening candidate antisense compounds. “Candidate antisense compounds” are those that inhibit the expression of a nucleic acid molecule encoding hypothetical tumor endothelial marker and which comprise at least an 8-nucleobase portion which is complementary to a preferred target region. The method comprises the steps of contacting a preferred target region of a nucleic acid molecule encoding hypothetical tumor endothelial marker with one or more candidate antisense compounds, and selecting for one or more candidate antisense compounds which inhibit the expression of a nucleic acid molecule encoding hypothetical tumor endothelial marker. Once it is shown that the candidate antisense compound or compounds are capable of inhibiting the expression of a nucleic acid molecule encoding hypothetical tumor endothelial marker, the candidate antisense compound may be employed as an antisense compound in accordance with the present invention.  
     [0277] According to the present invention, antisense compounds include ribozymes, external guide sequence (EGS) oligonucleotides (oligozymes), and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the target nucleic acid and modulate its expression.  
     Example 16  
     [0278] Western Blot Analysis of Hypothetical Tumor Endothelial Marker Protein Levels  
     [0279] Western blot analysis (immunoblot analysis) is carried out using standard methods. Cells are harvested 16-20 h after oligonucleotide treatment, washed once with PBS, suspended in Laemmli buffer (100 ul/well), boiled for 5 minutes and loaded on a 16% SDS-PAGE gel. Gels are run for 1.5 hours at 150 V, and transferred to membrane for western blotting. Appropriate primary antibody directed to hypothetical tumor endothelial marker is used, with a radiolabeled or fluorescently labeled secondary antibody directed against the primary antibody species. Bands are visualized using a PHOSPHORIMAGER™ (Molecular Dynamics, Sunnyvale Calif.).  
    
     
       
         1 
         
           
             149  
           
           
             1  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            1 

tccgtcatcg ctcctcaggg                                                 20 

 
           
             2  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            2 

gtgcgcgcga gcccgaaatc                                                 20 

 
           
             3  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            3 

atgcattctg cccccaagga                                                 20 

 
           
             4  
             5076  
             DNA  
             H. sapiens  
             
 
             
               CDS  
               (211)...(2094)  
             
           
            4 

acaggagagg gccccagcag ggccaccggg cggcaaggct cctctgctga acagcccctg     60 

ggcgggagac tcaggaagct gagcctgggg cagtacgaca acgatgctgg ggggcagctg    120 

cccttctcca aatgtgcatg gggaaaggct ggtgtggact atgccccaaa cctgccgcca    180 

ttcccctcac cagcggacgt caaagagacg  atg acc cct ggc tat ccc cag gac    234 
                                  Met Thr Pro Gly Tyr Pro Gln Asp 
                                    1               5 

ctc gat att atc gat ggc aga att tta agt agc aag gag tcc atg tgt      282 
Leu Asp Ile Ile Asp Gly Arg Ile Leu Ser Ser Lys Glu Ser Met Cys 
     10                  15                  20 

tca act cca gca ttt cct gtg tct cca gag aca ccg tat gtg aaa aca      330 
Ser Thr Pro Ala Phe Pro Val Ser Pro Glu Thr Pro Tyr Val Lys Thr 
 25                  30                  35                  40 

gcg ctg cgc cat cct ccg ttc agc cca cct gag ccc ccg ctg agc agc      378 
Ala Leu Arg His Pro Pro Phe Ser Pro Pro Glu Pro Pro Leu Ser Ser 
                 45                  50                  55 

cca gcc agt cag cac aaa gga gga cgt gaa cca cga agc tgc cct gag      426 
Pro Ala Ser Gln His Lys Gly Gly Arg Glu Pro Arg Ser Cys Pro Glu 
             60                  65                  70 

acg ctc act cac gct gtg ggg atg tca gag agc ccc atc gga ccc aaa      474 
Thr Leu Thr His Ala Val Gly Met Ser Glu Ser Pro Ile Gly Pro Lys 
         75                  80                  85 

tcc acg atg ctc cgg gct gat gcg tcc tcg acg ccc tcc ttt cag cag      522 
Ser Thr Met Leu Arg Ala Asp Ala Ser Ser Thr Pro Ser Phe Gln Gln 
     90                  95                 100 

gct ttt gct tct tcc tgc acc att tcc agc aac ggc cct ggg cag agg      570 
Ala Phe Ala Ser Ser Cys Thr Ile Ser Ser Asn Gly Pro Gly Gln Arg 
105                 110                 115                 120 

aga gag agc tcc tct tct gca gaa cgc cag tgg gtg gag agc agc ccc      618 
Arg Glu Ser Ser Ser Ser Ala Glu Arg Gln Trp Val Glu Ser Ser Pro 
                125                 130                 135 

aag ccc atg gtt tcc ctg ctg ggg agc ggc cgg ccc acc gga agt ccc      666 
Lys Pro Met Val Ser Leu Leu Gly Ser Gly Arg Pro Thr Gly Ser Pro 
            140                 145                 150 

ctc agc gct gag ttc tcc ggt acc agg aag gac tcc cca gtg ctg tcc      714 
Leu Ser Ala Glu Phe Ser Gly Thr Arg Lys Asp Ser Pro Val Leu Ser 
        155                 160                 165 

tgc ttc ccg ccg tca gag ctc cag gct cct ttc cac agc cat gag ctg      762 
Cys Phe Pro Pro Ser Glu Leu Gln Ala Pro Phe His Ser His Glu Leu 
    170                 175                 180 

tcc cta gca gag cca ccg gac tcc ctg gcg cct ccc agc agc cag gcc      810 
Ser Leu Ala Glu Pro Pro Asp Ser Leu Ala Pro Pro Ser Ser Gln Ala 
185                 190                 195                 200 

ttc ctg ggc ttc ggc acc gcc cca gtg gga agt ggc ctt ccg ccc gag      858 
Phe Leu Gly Phe Gly Thr Ala Pro Val Gly Ser Gly Leu Pro Pro Glu 
                205                 210                 215 

gag gac ctg ggg gcc ttg ctg gcc aat tct cat gga gcg tca ccg acc      906 
Glu Asp Leu Gly Ala Leu Leu Ala Asn Ser His Gly Ala Ser Pro Thr 
            220                 225                 230 

ccc agc atc ccg ctg aca gcg aca ggg gct gcc gac aat ggc ttc ctg      954 
Pro Ser Ile Pro Leu Thr Ala Thr Gly Ala Ala Asp Asn Gly Phe Leu 
        235                 240                 245 

tcc cac aac ttt ctc acg gtg gcg cct gga cac agc agc cac cac agt     1002 
Ser His Asn Phe Leu Thr Val Ala Pro Gly His Ser Ser His His Ser 
    250                 255                 260 

cca ggc ctg cag ggc cag ggt gtg acc ctg ccc ggg cag cca ccc ctc     1050 
Pro Gly Leu Gln Gly Gln Gly Val Thr Leu Pro Gly Gln Pro Pro Leu 
265                 270                 275                 280 

cct gag aag aag cgg gcc tcg gag ggg gat cgt tct ttg ggc tca gtc     1098 
Pro Glu Lys Lys Arg Ala Ser Glu Gly Asp Arg Ser Leu Gly Ser Val 
                285                 290                 295 

tct ccc tcc tcc agt ggc ttc tcc agc ccg cac agc ggg agc acc atc     1146 
Ser Pro Ser Ser Ser Gly Phe Ser Ser Pro His Ser Gly Ser Thr Ile 
            300                 305                 310 

agt atc ccc ttc cca aat gtc ctt ccc gac ttt tcc aag gct tca gaa     1194 
Ser Ile Pro Phe Pro Asn Val Leu Pro Asp Phe Ser Lys Ala Ser Glu 
        315                 320                 325 

gcg gcc tca cct ctg cca gat agt cca ggt gat aaa ctt gtg atc gtg     1242 
Ala Ala Ser Pro Leu Pro Asp Ser Pro Gly Asp Lys Leu Val Ile Val 
    330                 335                 340 

aaa ttt gtt caa gac act tcc aag ttc tgg tac aag gcg gat att tca     1290 
Lys Phe Val Gln Asp Thr Ser Lys Phe Trp Tyr Lys Ala Asp Ile Ser 
345                 350                 355                 360 

aga gaa caa gcc atc gcc atg ttg aag gac aag gag ccg ggc tca ttc     1338 
Arg Glu Gln Ala Ile Ala Met Leu Lys Asp Lys Glu Pro Gly Ser Phe 
                365                 370                 375 

att gtt cga gac agc cat tcc ttc cga ggg gcc tat ggc ctg gcc atg     1386 
Ile Val Arg Asp Ser His Ser Phe Arg Gly Ala Tyr Gly Leu Ala Met 
            380                 385                 390 

aag gtg gcc acg ccc cca cct tca gtc ctg cag ctg aac aag aaa gct     1434 
Lys Val Ala Thr Pro Pro Pro Ser Val Leu Gln Leu Asn Lys Lys Ala 
        395                 400                 405 

gga gat ttg gcc aat gaa ctc gtc cgg cac ttt ttg atc gag tgt acc     1482 
Gly Asp Leu Ala Asn Glu Leu Val Arg His Phe Leu Ile Glu Cys Thr 
    410                 415                 420 

ccg aag gga gtg cgg ttg aaa ggg tgc tcg aat gaa cca tat ttc ggg     1530 
Pro Lys Gly Val Arg Leu Lys Gly Cys Ser Asn Glu Pro Tyr Phe Gly 
425                 430                 435                 440 

agc ctg acg gcc ttg gtg tgc cag cat tcc atc acg ccc ttg gcc ttg     1578 
Ser Leu Thr Ala Leu Val Cys Gln His Ser Ile Thr Pro Leu Ala Leu 
                445                 450                 455 

ccg tgc aag ctg ctt atc cca gag aga gat cca ttg gag gaa ata gca     1626 
Pro Cys Lys Leu Leu Ile Pro Glu Arg Asp Pro Leu Glu Glu Ile Ala 
            460                 465                 470 

gaa agt tct ccc cag acg gca gcc aat tca gca gct gag ctg ttg aag     1674 
Glu Ser Ser Pro Gln Thr Ala Ala Asn Ser Ala Ala Glu Leu Leu Lys 
        475                 480                 485 

cag ggg gca gcc tgc aac gtg tgg tac ttg aac tct gtg gag atg gag     1722 
Gln Gly Ala Ala Cys Asn Val Trp Tyr Leu Asn Ser Val Glu Met Glu 
    490                 495                 500 

tcc ctc acc ggc cac cag gcg atc cag aag gcc ctg agc atc acc ctg     1770 
Ser Leu Thr Gly His Gln Ala Ile Gln Lys Ala Leu Ser Ile Thr Leu 
505                 510                 515                 520 

gtc cag gag cct cca cct gtg tcc aca gtt gtg cac ttc aag gtg tca     1818 
Val Gln Glu Pro Pro Pro Val Ser Thr Val Val His Phe Lys Val Ser 
                525                 530                 535 

gcc cag ggc atc acc ctg aca gac aat cag agg aag ctc ttc ttc cgg     1866 
Ala Gln Gly Ile Thr Leu Thr Asp Asn Gln Arg Lys Leu Phe Phe Arg 
            540                 545                 550 

agg cat tac ccc gtg aac agt gtg att ttc tgt gcc ttg gac cca caa     1914 
Arg His Tyr Pro Val Asn Ser Val Ile Phe Cys Ala Leu Asp Pro Gln 
        555                 560                 565 

gac agg aag tgg atc aaa gat ggc cct tcc tca aaa gtc ttt gga ttt     1962 
Asp Arg Lys Trp Ile Lys Asp Gly Pro Ser Ser Lys Val Phe Gly Phe 
    570                 575                 580 

gtg gcc cgg aag cag ggc agt gcc acg gat aat gtg tgc cac ctg ttt     2010 
Val Ala Arg Lys Gln Gly Ser Ala Thr Asp Asn Val Cys His Leu Phe 
585                 590                 595                 600 

gca gag cat gac cct gag cag cct gcc agt gcc att gtc aac ttc gta     2058 
Ala Glu His Asp Pro Glu Gln Pro Ala Ser Ala Ile Val Asn Phe Val 
                605                 610                 615 

tca aag gtc atg att ggt tcc cca aag aag gtc tga gaactcccct          2104 
Ser Lys Val Met Ile Gly Ser Pro Lys Lys Val 
            620                 625 

ccctccctgg acccaccgat gcctctcgaa gccctggaga cagccgttgg gtgagggtgg   2164 

ggcccccact ttttaccaaa ctagtaaacc tgacattcca ggcccatgag gggaaagagg   2224 

atcttccagc tctgcaaaaa caagaacaaa caacatcacc gtgaattggc ctttcctgaa   2284 

agtgacttat ctgacacatc tctgtagcca catgcttttt gggtagaaga agctgggcat   2344 

gggtgcaccc caccccctag ggtccccatg ggaaagggac atgcaaggaa acagcacaga   2404 

acacgaggtg gtccccatgt ccctggcaca ctagcattct gggggatgag gaatccccag   2464 

cccttgaggc agaggtgccg agtgactgcc atgcttcgcc cgtccgcatg ggcgcttctg   2524 

tccagctgca cccgaggccg ggggtttccc tcacctcggt cttcccaaga tggagatgct   2584 

aacgaaactg agaagggggc gtatgtttga cgaaggtttg tgcaagtcag gcccttctgg   2644 

aacacagcag ggcctacaac gaggggcctt tgcgatgggc tgtgaggatg ggggtggtgg   2704 

gaagaattgg ccacgttaga gaccccatgc caccccacca tggtgagtgc tctgtgcctc   2764 

ctgctcacct gtggtgagct gggcgagctg ggcgagctgg gcgagctggg ctggggagag   2824 

cctgtgagga ccgagaggag aaatgagaag aaggaacaaa aatattattt ctatgtaatt   2884 

tatattttac ttatgccaaa ttatttatga taatttgcca ttgctatact gtaccagtgt   2944 

caaatgctgc agcctgccaa gctgtgattt tgtgaggctt gtccctatgt aggatgcacc   3004 

gcaggcccct ggccactgaa agagtgtgca gtggactgtg ggtctcccat atgcggtgcc   3064 

gcccaaaggt ggctttgcct caagcaacct accctgatgt tttactcatt ggaatgtttt   3124 

tccccgattg tggatgactt cttttctgat ggagagagtc caggagggat ggaaaactcc   3184 

tggatttaag ctcagcatcc cccacatggg cttttcgatc atcttcaggc ctgaagctgc   3244 

acgacctgaa gttcgcctgc atttatcagc cctctttgtg ctgctccttg ccaccttggg   3304 

gttcctgctg gggaccatgt gtggttgtgg catgtgtgag cagaagggag gatgaggaaa   3364 

aagagaagaa accccggtac tgacaagctg tttttgagtg ccactgtttg ccatcatcta   3424 

agccactgaa tcaagtgtat ttcaggctta tttcaacatt ccaatgccct ggttttcctg   3484 

cttgaatctg ttcgtggtca aaggtttggg ggaatttgtg accctggaac atccccagag   3544 

tgaaagatgg agctgggcca catcagaata aggccttggc cccatcctct cacagcctag   3604 

gtgctctgca ggcatgctga ctgtcctgat tgcgatccag cccgaaattc cctcctctgc   3664 

tttcaaaagt caaatccccc attcttaggc cacactggtg tcacaagctc ctgtcaggga   3724 

gctggggttt gggaatgtgc tttgtgaact ctgctttaaa gtgaggggcc gaggaaaact   3784 

tagaaacagg cagagttgga agcagccaaa tcacagtggg tgttgtgtgt gtgtgcgtgt   3844 

gtgcatgcgt gcgtgtatgc gtgtgtgaaa gcaggtggac cattccactt tttagctcct   3904 

attgatgcac caaaccaagt gcctcatttc tgtgccaaat gtttgccttg gtcgttgtgg   3964 

acctccttct ctaacttgcg gtggcatgac tgtcaggagg tgctggcatt ttcagcagat   4024 

cctcatgtgt tgaccctgat gtctttagca gaggcctcta gcatctcggt ttttcatcca   4084 

ctgcaggaat gtggccacag ggagcagagg tttgtacttt ccccaagagg tcctcatcct   4144 

gagacggtct ctacccatgt ttaacccaaa gagtgcaggc caggttcctt atccttctga   4204 

tgaaggatga gagagctcat ttagaagtca gagcaaacta gggtctcagt attgagaaac   4264 

gcagcctgcc agggaatcac agagacatcg gggtgcccgc gatggccctc atgaagccat   4324 

gcctcgacgg cattcaggaa gccctgcaaa cgtgcttttt gaactcattg gccaggtgtg   4384 

atttttacac aaggtaaacg tggtcaaggg catcggggaa tttgctccaa gcagatagct   4444 

ccctctgagg aaccaaagga agcaagtttc catgatttct gaagagctgg tataggaagt   4504 

ttctttcttc cttttgtgtt acatgtgcat taaacagaac aagctgtgtg tcatcacaga   4564 

ttgtactgtg ggctcagaaa ccgtgagaga gcccccaccg tggacaccgg ctctagggcc   4624 

acaggaaaag gaacgtttcc aggcattttg tctccatgga caggcacgta ctgccctggg   4684 

gagtaaatgc ggagagttca cgaactgtgc ccaacgcatg ttatagccag ggtcctacta   4744 

actactcagt aaaagaacgt attgttgtat tcctccagtg ttaagctata gccatgttaa   4804 

aagtcactgt gcatttattc tcagcatcaa ataccttgta acgtcttctc tgccttgtta   4864 

gtgcatattt ttacttttct gatactgtaa agaatatatc cagtatgtaa atgaatgttc   4924 

tataaatctt ttgtatagtc attttctctg ctccttaaat atcatctcta ttcagagtat   4984 

aataaaatta tgaacttggt aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa   5044 

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa                                 5076 

 
           
             5  
             21  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            5 

ctgggccaca tcagaataag g                                               21 

 
           
             6  
             21  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            6 

cgcaatcagg acagtcagca t                                               21 

 
           
             7  
             26  
             DNA  
             Artificial Sequence  
             
               PCR Probe  
             
           
            7 

cttggcccca tcctctcaca gcctag                                          26 

 
           
             8  
             19  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            8 

gaaggtgaag gtcggagtc                                                  19 

 
           
             9  
             20  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            9 

gaagatggtg atgggatttc                                                 20 

 
           
             10  
             20  
             DNA  
             Artificial Sequence  
             
               PCR Probe  
             
           
            10 

caagcttccc gttctcagcc                                                 20 

 
           
             11  
             95001  
             DNA  
             Homo sapiens  
             
 
           
            11 

ccaggagaag gcagagttgg accagctgct cagtggcttt ggcctggaag atcctggaag     60 

ctccctcaag gaaatgactg atgctcgaag caagtacagt gggacccgcc acgtggtgcc    120 

agcccaggtt cacgtgaatg gagacgctgc tctgaaggat cgggagacag acattctgga    180 

tgacgagatg ccccaccacg acctgcacag tgtggacagc cttgggaccc tgtcctcctc    240 

ggaagggcct cagtcggcca cctgggtccc ttcacctgcc acaagagcag ccagaactca    300 

ctcctatctg acggttttgg cagcaacgtt ggtgaagatc cgcagggcac cctcgttccg    360 

gacctgggcc ttggcatgga cggcccctat gagcgggagc ggacttttgg gagtcgagag    420 

cccaagcagc cccagcccct gctgagaaag ccctcagtgt ccgcccagat gcaggcctat    480 

gggcagagca gctactccac acagacctgg gtgcgccagc agcagatggt tgtagctcac    540 

cagtatagct tcgccccaga tggggaggcc cggctggtga gccgctgccc tgcagacaat    600 

cctggcctcg tccaggccca gcccagagtg ccactcaccc ccacccgagg gaccagcagt    660 

agggtggctg tccagagggg tgtaggcagt gggccacatc cccctgacac acagcagccc    720 

tctcccagca aagcgttcaa acccaggttt ccaggagacc aggttgtgaa tggagccggc    780 

ccagagctga gcacaggccc ctccccaggc tcgcccaccc tggacatcga ccagtccatc    840 

gagcagctca acaggctgat cctggagctg gatcccacct tcgagcccat ccctacccac    900 

atgaacgccc tcggtagcca ggccaatggc tctgtgtctc cagacagcgt gggaggtggg    960 

ctccgggcaa gcagcaggct gcctgacaca ggagagggcc ccagcagggc caccgggcgg   1020 

caaggtgagc tgggtctcca tgggaggtgc tccacgggag gtgctccacg ggaggctaat   1080 

gtgtgatgag aaatcagcct agtaggttag cttttggcga aatccacaag ggagggacat   1140 

ttcccttgca gtttcaactc ttgtgaattt tggcctagga tccaaatgct gtcatgctgg   1200 

tgtggtccct tggtaggaga tttggaggat gggaagaacc aggcagaaga cttgctgtta   1260 

acgtcagtgc aggggcaggg acagcatgct ctctgctgga aagggccggt catgcctcca   1320 

ttgcagaatg ggcttaacag tgaaaccatt cttccttcgt gaatgttggt ggatttacaa   1380 

agaaagcata cttacttctg tccctgcggt ataggtcagg gctttgtgga agaatgccag   1440 

gtacttcagt ggggctgaag gttggggatg aagaagacta ctgagccctc agacagcttt   1500 

ggcacaagga attgattaag cagtcgtggt ataaaatgtt ctgattacaa atacacctgt   1560 

cagagttggc cgtggtggtg tggggagact ggttatggaa ggcagtggct gggcagaggc   1620 

ctggggtcca caaggggttc tactgtggag agcagctcag tgatgggagg ggcttggggg   1680 

aacaggccca ggggtgaggg gactgagagc tgtggtggga cccaaagcca tgggacccgg   1740 

tgcggggcct ctggggatgc cccaaaacca ggccggggtc atgctaactg cagggaggcc   1800 

aggactgcac atgtcctttt cccgtgaggc tggtggtttg gaaaccagca cagtgccttt   1860 

ctgtgcagcc ttgaggcctg ggaggaacca gggctgagag tggtggacag gcagtgacat   1920 

ctgcctgggt tacagcagca ctatcttcaa gctgcatcga tgtaatgggg caagttgcat   1980 

gttgggacca ggttactata cagtgttctt tctgttggga aagcatgaag gctgagggga   2040 

ccagagagct ggaggtggtc aggtcggcca gggaaacact cagcaggcag agaggggcat   2100 

tgggacggag cagggttgtc tcaggtaggg gactgtgtgg gtgagatcat gtggtctgga   2160 

agctcctgca cagaggtgca cgccaggaga ggacggccag gctgtagcgg ctgtgcctgc   2220 

gggcactggg aggctacaga aggtggagag acagagctgt gttctgggag ccctggcagt   2280 

gccatgcaag gaccaggacc caaaggataa ccttgggcca gaaagtgtgg catccgtgtg   2340 

gtgccagggc ctcccacatt ggcacgttgg ggtgttttgc catctggggg ctgctggctc   2400 

cttagaggga cttgcctcta aaagtgaaga ccagagaggt aaaggacaag ggacatggct   2460 

gtgtgacgcc gtgcatgtga ttcccaccat gtgctggtaa cacggatgag agatgctacc   2520 

atttatgctg gcgtggttct tggtttaggt gtgctggccc atgtcatcgt cctaagcacc   2580 

ccggctgcag gcaccagtct ctgccttaca gtcgtgttga tggaggtgtc agtagattat   2640 

gtggcctgcc caggttcaca tgggacctgc atagtagagc aaaagtcagt gccctgaggt   2700 

gtggactcag tgtctccatc ctctttggag tcacacaggt gaggactgca gtcccgactc   2760 

aggtctgggg tggcctgggc gaaggagcac acaccctgca gatgttggtc ctggcttcag   2820 

gtctgagtgt gctgtgggtt gcctgagtga tgcaagtggg taaagggcag cgtctctgtg   2880 

aatttctctt cactccatct gtgagaagga aaccctatcc cagtgcctgg cccggggaag   2940 

gtgtgaagaa acgctcgttc acatccacct ttcatgtact aggtgtgtga ctgagcaaac   3000 

agctgtcatt ccagcttgcc tgagtaactc cctctttgta tgtcatgtgc tgggagttgg   3060 

aaggagcctg gagagtcccc catgagtaga ttattggact ttacaataca gccgtatagc   3120 

aaccacaaca ccacagcagg gtagcagtcc ctgaacaata ggtccaggtc gatgcattaa   3180 

acaaatatat ttgggaaatt ctgagtttac taaaaaggct ctaatgggaa aaaactatct   3240 

gcagtatcat acctgactta cttcaccaaa ccttcttaaa agaagttact tggaaacatt   3300 

aaaatcagaa gtcttttctc ctggataaca atctcatgta ggtttggagg aggctggagg   3360 

catctgagtg tatgtggaga agaggactcc acatacttag gttaacatat agtagtctct   3420 

tggcttaggt taacatatag tagtctcttg aggttaatat gtcttccaat tgattgaatt   3480 

caatccttag tgattccctg ttcttgctgc aaagaaacag ttataaggcc tggaattttc   3540 

gaaagccaca tcatattatc caccctcagt ttggctgttt ttaaattact tggtaaactc   3600 

attactttat ttttttattt atttttttga gacagagtct cactctgtcg cccaagctgg   3660 

agtgcaatgg cgtgatctca gcttactgca agctccacct cccgggttcg caccattctc   3720 

ctgcctcaac ccagtagctg ggactacagg cgcccgccat cacgcccggc taattttttt   3780 

gtatttttag tagagatgga gtttcaccat gttagccaag aaggtctcga tctcctgacc   3840 

ttgtgatccg cccccctcgg cttcccaaag tgctgggatt acaggcatga gccgttgctc   3900 

ccagccaaac tcgttacttt gagaacactt tttttttttt tttgagatgg agtcttgctc   3960 

tgtcgcccag gctggagtgc agtggcacaa tcttggctca ctgcaacctc cgcctcctgg   4020 

gttcaaatga ttctcttggc tcagcctccc gagtagctgg gactacaggc gtgcacctcc   4080 

atgcctggtt aatttttgta tttttagtag agatggggtt tcaccatatt ggccaaggtg   4140 

gtcttgaact cccgacctca cgatctgccc accttggcct cccaaagtgc tgggattaca   4200 

ggcatgagcc accgcgccca gcccaataac acattttgat tttgatttta gatactcttt   4260 

aatgcgtttt attataaaag ttatttaatt atcattttga agtctaagga ctttcatatc   4320 

tcaacaacag accagtaaaa ttcagtgcat atttgggtat tgacaataca aatttaaagt   4380 

atttattaat ctattcatat ttgacaggca tctggggcca ttggtccatt tttttcatag   4440 

cttcagaact aaaaagatgt cagaagatta ggtataagca aaactggtta ccagtctccc   4500 

cagagctttt taaaattggg aagtgacctt cttgtaggaa ccctgccaca catgagcaac   4560 

tgtccatgag cagtgatgaa tggacactga agggttagcc gcagcattgg aaacagggca   4620 

gagtgagcca tgcccttcct gggagctccg cttcctcttc caggacgtgc ctcttgtgct   4680 

aggtaagcac caagctggga gatggagcaa gccttgagac ttgcacttca tttagtgtca   4740 

aaagcctgca cagtgtagag gtggtctctg aacagcctgc atggcaggct tttggatctc   4800 

agtccaagac tttctgacct gatagaaatc ccattaaaag atgcttactg ggccgaggca   4860 

ggcagatcac ctgaggtcag gagttcaaga ccagcctggc caacatggca aaaccctgtc   4920 

tctacaaagt tacaaaaatt ggtcaggcat ggtggtgcat gcctgtaatt ccagcttctt   4980 

gggaggctga ggcaggagaa tcacttgaac ccaggaggca gagattgcag tgaactgaga   5040 

ccgtgcactg cactccagcc tgggtgacag agcaagcact ctggcccaaa aaaaaaaaaa   5100 

aaaaaaaaaa ttattgctta cttctgtagc tctcaggcac tgcagctaag caaggaagga   5160 

attgtttctt ccctcactag caggtataga aaacactgga actcttttga ttttaaaatt   5220 

taaatttcag tattgacatt tctcaatagg aaatggctac tttggcaagc ggcagaaaac   5280 

aaaaattact agatcctagc agggacacgc gtacaagtgt ggtagcaaag cagctagttc   5340 

cgagtccctg ggacatcgtc agaaggttgg ggatgctgct ggagtgcctg cactttgaag   5400 

gtgtcctaga tccctcaatc catatccgtc tcctcagcca gccaaaggag accagggctg   5460 

ttgagctgga gccctcctct ttcagcttag atccatgtgt gaataggaag gattctggca   5520 

cgtccaaaag gctcatgaca tgcccagaat ggtaccatca cctaaccctg caaggggcat   5580 

catttccaca tctgtgtgca tgaggttcag ccccatagat agtgtggcat tgcctgactg   5640 

actggagact accttgagtc tcgctcacaa ggggaaacca tagactggaa gttctgagag   5700 

cactatgtct acatgagccc cttcttgctg gcctgccttc catctcatcc ctggacacaa   5760 

actgctacac aactttctta attctgactg tggatgaagg tttgtcacag agacctcagc   5820 

atcctgaagt taccagaatc tttcactatt tgcagattat gtcctcatta tgagaaagac   5880 

caccacttgt ggtagagagt tgggaatagc attgccctgt gctcctccgg gggacttctg   5940 

tgcatcctgc attatttatg agatgaaaat tatatgtgaa ggctaagtat ttcctgagaa   6000 

agtctttcat accagcacca taataataat agtggtgctg ctgctgatgg tggtgatgat   6060 

cacagtgatg gtgatggtga tgatgatggt gatggtgatg atggtaatga ctgtgatgat   6120 

attgatggtg gtgatggata tggtggtggt gttgattgta atgatggtga tgttgatggt   6180 

ggtgatgatg ttgatgttga tggtgatgac ccttatgatg gtgatgactg atgatgatga   6240 

tggtgatgat gacagtgatg atggtgatga tgatgatgat gatgatggtg atgactgtga   6300 

tattgatggt ggtgatggtg gatgatgacg gtgatggtgg tgatgatgtt gatggtgatg   6360 

gtgatgaccc tgatgatggt gatgactgtg atgatgttgg tgatggtgat ggtaaatgac   6420 

tctgatgatg gtggtgatgt tgatggtggt gatgatgtta atggtggtaa tggtgatgtt   6480 

gatggtggtg atggtgatgg tgatgactgt gatgatgttg atggtggtaa tggtgatggt   6540 

gatgatgaca gtgatgatgg ttatgactgt gatgatggtg atgatgctga tggtggtgat   6600 

gatgctttgg tgatagtgat gatgacggtg atgactgtga tgatagtgat gatgtttatg   6660 

gtggtgttag tgatggtgat gttgatgatg ttggtaatag taagaactgt tactctgagt   6720 

gcctacactg ttttaggtac cttcatttca ccaggacacg taacagagct ctcgtctctc   6780 

tgactctgca ccccatggct atgtcctaat tccactaaac tcacactctt acaccagcca   6840 

gtaaacctgt tgagggaagt gctcattatt ttttttccct ggcatgcagg aagagttcga   6900 

catatgtttg caaatacagg ggtctgggac aggcggaact gcaaatgatc cttttgagac   6960 

ctgaactact ctgctgaatg ggcactgagg ggagatttat cgctggacag tgtagagtag   7020 

ccctgcccac ctacaagatc agagagaggc cctccagagg tggggtatca caaagctctg   7080 

gtggctgaga cctgggtgct ctgtgtgcca gtgagcacag ttttgtatcc ttcttgtaga   7140 

atgggtgaga ttcagggagt tggtttgggg acattttact ccccacaagt gcctgccagc   7200 

catgaggccc tgctccctca ctctggtctg acttctgctg ccactggtgt tttgtggaag   7260 

agcccctggg tgctgctgcc aggctcattg tccccgcccc actctgggtc tcagcctggt   7320 

ttcagcctgc acgtggtggg ttttttgtat catacccttt taagtgggag aatatttcaa   7380 

ctgatgatat cccagtaaca aaagaaatga ctcaacctgt gaaattcatg attccgtggg   7440 

tggcaaaaag ccagttctgt ggtttttttt cataccttga gggctctttg cttcatgttg   7500 

tcaaaatatt ttattcatgt tacatcaacc tccaccctgt gatgacagca acctggcagg   7560 

ccctgttctg cttgcagata gtgctgtggc attcccacca ggcatttaat gtccctccca   7620 

gactcggcat ctgctctgtt agtgctaacc catggctgat aacctgtgca tcctaaagaa   7680 

agttcagagc aatggaaact gtaagctttt aataattgac catggagagc ccgttgattt   7740 

aaattgtgtg ctaaacccca accaaaggaa ccaaatgtga aagctggaag agcgctttag   7800 

gattcagaaa gcagcttatc tgcaagctct gattccgtgg cagaaggctc acagcctcac   7860 

aaagtggaga caggcagaca gtcccacctc atttcaactc cagagttggg gaacgtgctg   7920 

ggggtgctca gccagagcct ctcagccagg ccttgtgagg cagagggatc cttaccaggc   7980 

agatggtctg gaggagaggc agaccgggag aaagcatagt gtgccaggga agttcagtgc   8040 

tggggagtga ggctggagat gcagataggc cccaccatgg agggccagga tgggggccaa   8100 

ggagtgtggc tcttccctga gggcagaggc gagccttggg gtcttgggct gggcccttgc   8160 

ttgttttttt tttttttttt tggcatggtt actgtcttac cagaagagaa ggcactgaga   8220 

aggtgcactg agcctgggag ctctattagg gtcccagaga caatggagga tagcatttag   8280 

gcaggatggg ggttccatgg ggtggcattg gcctccaact ctgcagagga agaatctcag   8340 

gagggaggga gggaagtaag caagtgggcc ccagcgcctg cgcccgtagc agctggacat   8400 

tggaagaatg aaggggcctt gaatttggct attagtgatc tgggtatggg ggtttcagat   8460 

ccgtgctagg gacacagggg atccatggta ctttctaaaa gtccaggtgt cgttatttcc   8520 

gtactgtgtg ttataactga gcagtgccca gttatgggca tcatcctgcc agtgccgggc   8580 

cctcagagca tgggggaaga cagcagcgtg cgcatctgag gtggaggatg gaggagtgac   8640 

cgcagcacca ggcatagaca ctcctggagc cctccaagga ctcaggcgtc agcaagagac   8700 

cagggctgat ggcagcacct ctgccttttg ggggctgtct ctggatggtc tcagtcagcc   8760 

cagggtcacc tttattctga gatgcttccc ttggccacca ccccctccag ggagctgagt   8820 

gaggtcctag gacccaggtc ttataaaggg acttcctggt actcacatca gagaaccagg   8880 

atagaggagg tctgggagcc aaggagccag ggccccgggc gctggacatg cgtccgtgag   8940 

ggactcttgc tctttgtttg ctaccactgg caaaacaagg ctttttctcc atctgtgagc   9000 

ttcagtctct ggaggtttct gagagagatg ggatatttat gtgccttgag aactctgaaa   9060 

agagactcct gcccaggggt caggactaga cacagctcct ctccaccttc agaccccgat   9120 

gctttagggc cgtgggtatg aacaggtcat gtgtatgtga gtgcacattt aataaccgag   9180 

tcagcccact gcactgcagg gagctctgtg ggtgtccaat tcggaaaacg ttttagaatg   9240 

agaaactcca gtctgcttgg ggaaactgcc attgcaatta ctttcttttt attgcataaa   9300 

accaactttg aaattttaga gttgatgaag ctttccattt gccccagata ctctcactct   9360 

gcaaagcagg gggccttggt ttcccaccct accaccttgg tgggcgctct gaagacactg   9420 

ctgagaggct agggccacag aggagaaggt gctatctggg ccttctggga ctttgaggtg   9480 

tggattccag cccaccttct gctcagtcca cactgcccgt gatagctaca tcaagggacc   9540 

ttcactggtt caggcccaaa atgaagtatc gtttctataa cagatacctt ctagcgccat   9600 

ctttactctt ctgagatgaa agtcatagcg aatataacct ccttaagcac atactgaaaa   9660 

ctaaatttaa caccctaaca ctcatgtcaa aggaaaaata aaaagaaagt aattcacaat   9720 

aaagtcatat gaattttgag atgaaaatct ttggtccggc ccacagtaga aaacagaaat   9780 

catccctcag gtttaaaaaa tactcattaa ttttttattg tggtgaaata catgtaacat   9840 

aaaatttagc attttaatca tttttaagtg tactgttcag tggtagtaag gacatttgca   9900 

ttgctgtgca accatcatga ctatctagtt tcagaaattt gtcgtcatcc caaagggaaa   9960 

ccttataccc cctgaagtca cttcctgtcc acacctccct gccaaacccc tggcactcac  10020 

tcatcccctc ctgtccctgg ggatgtgcct actgtggaca ttttacataa atggcatcac  10080 

aaagtatgtg ctttttgtgg ctggctcctg tgacgtggtg tgtgatgttt tcgagccgga  10140 

cgtgttacag cccatgtggg aacttcagta ctgctcctgg cagagtaata ttccacagct  10200 

gggatagagc acagtttgtt tattcattcc tctctcgatg gagacttggg ttgttcccac  10260 

ctttggcctc ggtgaatggt gatgctgtga tcatgggtgt gcctgtgttt gtctgaacac  10320 

ctgctttcag ttgtttgggg cgttacccag gagaggggtt gctaggtcct gtggcacctc  10380 

tgtaacttgc tggggaactt ccccactgat gcttgaaagt catttggtat caccaggtct  10440 

ctggggtgtt tcatttgtcc ccagaagctc tgcctaagct gcactgggag tgggctgatc  10500 

tgtgtgaccc taacggcctg agtgctggct caggggaact gctaatttat ggaatcctag  10560 

gtaggtggtg gtagaattct ctccctctgt cagggtggag cagttacgac aaatccacag  10620 

tctcagggac ataaagcaac atggtctttt tccaatcatg ccacatgtcc actgcattgt  10680 

ggcttgacat gggcctcatg ccaggacctg ggatgagggg tgagccctct ctgtgcaccc  10740 

aaggctgccg acactcccga gagcactgcc ggctcccacg gcttctgcca gaagtcaccg  10800 

gctgcgtcgc tccccacagt tcatcagcct ggtggacctg tggccacact tatgttcagc  10860 

gcagcccatg tggccctgaa ggtggacagc ttttgtatcc gtactgaggc atgggataat  10920 

aaacgccaca gtgattaaaa gaggaaatgt tggccaggcg cggtggctca tgcctgtaat  10980 

cccaacactt tgagaggcca cggtgggtgg atcacgaggt caggagttca agactagcct  11040 

ggccaatatg atgaaacctc atctctacta aaaaatacaa aaattagccg ggcatggtgg  11100 

cacgtgcctg tagtcccagc tactcgggag gctgaggcag gagaatcact ggaactgggg  11160 

agacagaggt ttcagtgagc caagatcata ccatttcact ccagcctagg caacagagtg  11220 

agactccgtc aaaaaaaaaa agatgaagtg ttagtggaag aggccagtaa ggtcacgtga  11280 

tggggggtga tccaaaaaga aaaccaatgc atgtgaacag gcaggcattg aagcctgtac  11340 

agaagcccca ttgatgaggt atttggggcg gggcagtgtg tgaggcaggc gggggtcccc  11400 

cttctgtggt ttgcagcttt tcacatctgc acgtaaggtt acagttgact tacaaaacat  11460 

ggggtattgc tggcatttct catgttggag ggcttcgttg tgtggacgta tcatttccct  11520 

tttaaatatg cctttttaga agaaatgcca ccacctagcc atggacttca gtgtttccca  11580 

gtggaaagaa ttttcaattt tgcaatctaa aaaatgggat tccccccttc cgccttctgt  11640 

tgcagttttg ccggcgccta cccgttctct tagaatcagg gttagacatg aagacagcac  11700 

gactgaggga gggtgggcct gggaggggaa ggctcttccc tgggttggtc ttgatatgtc  11760 

cgtcagaacc ctggctaatg atttcctaac acattacgct gtaaaaaact gcaagttgtg  11820 

cggctcttta aggctatgcc ctccacgtgg aaggggctgg tcaatcagtc ctgtttcagt  11880 

tttgggagaa gactcctaaa accatttctg ggagcatttc agctgggagg agtgttgggg  11940 

catccttgtc atgccaccct gcctcctttt acacactgtc tcgaaaagat tagtgtgtgt  12000 

gtgtgaatga gctgaagtct ggaggcctca agctcaccgt gaagcagtct ttgcctgtta  12060 

tttgttttca ctcctaggaa tgcaagggag cttccagaac ctatcaggca cacctgtgtg  12120 

atgtcgcgct ttattcctag aagatcacat caagataaat cagtagctta tggggacttt  12180 

accttctagt gcccagatag aaaatgaaag aaggcatgtt ttaaaatagg taatgttcta  12240 

gcatgtcatg agttttcacc tgttcttatt ttttaagtta attaattaat ttatcatttg  12300 

agataggatc tcactctgtc acccaggctg cagtgtagtt ggtgtgatca cagctcactg  12360 

catccttgac ctcctgggct caattgatcc tctcacctca gcctccagag tagttaggac  12420 

gacaggcatg tgccaccatg cctggatcat tttttttttt ttttgtattt ttctgtagag  12480 

actgggtttc atcatgttgc ccaggctggt ctggaactcc tgggctcaaa agatccaccc  12540 

tcctcagtct ctcaaagtgg tgggattaca ggcgtgagcc actgtgcccg gcccctgttt  12600 

tttctatgtt ttaattaact tatttatcat cgtatttatt taaggtgttt aacatgatat  12660 

tttgtttgtt atatctatac atagggagag gatcactaca gtcaaaccaa tggacatatc  12720 

caccacttta cctagttact tttgtgtaag agcacctaag gtctactgtc ttagtcaata  12780 

ttgcatcctg aagatttgct cagggagcgg attccgtctc ttttagaaca gaggttggac  12840 

actttgtctt gcatgttgga gtcacctggg gagctttaaa aatgcagacg ctaaaaatgt  12900 

gggtacctgc ttctacctcc agagggtggc agattgagtt ggccctggtg gggcctggat  12960 

gtcagacttg ctttaaaaat gctccccaaa taatgcagtg ctaattcagg gttgagacct  13020 

gctgtgattc ttgagcttgg ttgtgtgttg gaaacactag ggagttttta aaaatactga  13080 

cacctaggtc tcaccgctgg aggttctgac ttcacaggtg aggcccgagc tttaggattt  13140 

tagtgataaa aggtggacaa tggcctttga gaaccactgt tgtatatttg cagttctcaa  13200 

cttaggtgcg tgtcccagcc tccaggagag ctggcccttg gctcattgag gctggaacgt  13260 

gccgcagggt ggttctaaga tttgtgaccc tgctgtggaa tttagaggac agccaacagt  13320 

cacgtattgg ttatcagagg cagaggcagg cgaccccatg ggctgccttc cacctgggtg  13380 

ctggctttat ttcaccaggg cagagtgggc tatgtgaccc cacagtggag agaatgcagt  13440 

gacatgaagt gtgtgagtgg gcagcatggt gggtgtccgc tcctgaacac ttgacccatc  13500 

ttccttcccc tccctcatcc cacttcccag cagagcctca gggcctggga tctgccaggc  13560 

cgtgcgctgg caaagatcag tctccaagag cagtctgaat cacagaatca cagctcaggg  13620 

tcaacataag tactgactta cctatcagga tgtgttattt tacactctca attagtttac  13680 

ataattggga gttcagtgta tttggacaag gtggaaagtt gccgaagagc tttgtgggtg  13740 

ttttaaacaa aatttaaaaa acattttctg gctaagcgat ctgagaagcc ctctcctgca  13800 

cttcagactg ctcaggggtg aattgatggc aacagtgctg acccccaggc tgggctgagt  13860 

tcagtcccac atgtgtttag tacagcaccc agtgtcttgg cctgaatccc tgattctcca  13920 

gggctctgac ggcgatgcat ccccttctca cgaggcccct gggtgccccc agtcaaggac  13980 

tggctttcct gctctttcct cagagcacgt gaggattccc tgtcaggacc gtcccccacc  14040 

ctgttgtggt ggctttggat aaggtacgtc ataggatgca cctggggctg aggccccacc  14100 

atccccagct cctcctgtgg ggccggaatg actgagcgtc ctcctgcctc gcaggctcgg  14160 

tgtccttttg caccctgtgg tgaatcccag atcccgctgg gcgtggcgga gtctcaggtg  14220 

accctgcgca acttgctggc tgggcagccc tcagcacgtt tccttatctg tccttgacgc  14280 

cggctccacc cgtgaataac agtgagactg ctaaatgagg aaacatgctg gtctttggga  14340 

gtggcagtgt aggggacttt ggggcatgtg tcccatttta tactcaaggt cacgtggttc  14400 

ccgaggctct gggtgggtag cacccagtgt ctggagggaa ggaggcttgg gcgaagacag  14460 

ctaaatgcct ggtgtgggga ctgcccaaag agatgggcag cgtccagtca tgtgaccttt  14520 

ggagaccatg ttaccatgtc atgttttggt ggacaatgag cgtgtcaccg cgacaagagg  14580 

ggcacaagac tgtgtaaaga aaaagccact gcctgtccct ccctccacag agaccccagc  14640 

tgcatggagt gggtgaagct gcacatcacc tgcagatcac cggggtctgt gttcactggg  14700 

ggtttcaagg ggcctgagat ttctgcactg agtactcatg acctttgtaa ggagaggatg  14760 

caggattttt tttttttttt cctggctggg aactggcagg gaagtaaggg cagctcttcc  14820 

ccagcacctg ggcctcaggc tgggagcagg gtgggcacag gtgtgagaga tcagggtgtg  14880 

tgtgccatgg gtgcagccag atgcaggtgc ccccctgccc caccccaggg ctttgggagc  14940 

tgccctttgc ccgtgaacat ccctgtgtgg gagcttgggt tttgttccct ttctccttgg  15000 

tttttctgag aaggggtacg ttggggagct gggggtggga gggcggatcg cccagagccc  15060 

tgcaggtgct ctccagtgct ggcaaattcc ctcttgtccc cttatcagct ccttccagag  15120 

gtgacagcca tctgtgtggt ggcagctctc tcctgctccc atgaggtctc ctttttcttc  15180 

tcttttcctg gatttgactt cttaactgaa cagaaaaata tataggcatg gacagttttg  15240 

tagtagtgtt tggagaatag gccttaacaa tataattatt caattcatga tttcattgtt  15300 

caaactgccc aatctcattg cattacggcc agttctttgt cgtaccttgg aatttgtgtg  15360 

tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgttttgt cctctgtgtt tgtttgtttg  15420 

tttccttttg atgcatataa tgtaatattc ttggtgaagg ccatacctcc cctttctgca  15480 

ggtgtgagtg ggagggctgc aggttgcgga gtgagacctg aggctacact gctggcccct  15540 

gcagttttac cagaagctca aggataggat ggttgtaggg tgaggcccct tgtggtccca  15600 

agcaagacca gggcagctga ggagggtgga ggaggagggg tgctgggctg tggtaggagg  15660 

gaggctaggg gacaggaaga gactgcttca ggtgctggtc atttcacatt gatgtgaagt  15720 

gtgtaagaag taattgatgg actcaaacaa ttaaatgatt ccctcgggga gtgctcagga  15780 

attaagcctc agtgaggaaa aagaaatgta aaagtcatgt gtgtcttcat tgagatatgt  15840 

ggctcttcac aggttccagg gagcttggtt tgcttccata tgtttctatg tgtttttcta  15900 

atcttctgca atgatagaac atcatactaa agaaaaccat aaatcagtca ctttggaaga  15960 

gagatttggg gtagagagag agtgttttac caagtgctag ggcctccttt gggtttaatt  16020 

cagaagtcag tgcctcagcg ccagggctcc taacctgtgg cctgggctca cctgttcacc  16080 

cctcacctct tcaccccttc agagctcacc gacttagcaa agaagtactg aacccgcagg  16140 

gtgtctcagc ttggacagac tttggagctg aataagacct gatccttgtc cccacctggg  16200 

acagctggct gctactgcct ctgtcctcag aaagcaatcc aagagctctc tgagctggca  16260 

gtgcagaggt acggagcttg ctgtttatgc agaccttctc tggagaggtg agcattgatc  16320 

ctggtaggca gcgtaccaga gctagcaaat gaaccgcctg aggaaatgtc cccaagctgt  16380 

ggcctctcat aggtcaccca gacatcagag tgtgaagcaa aagtgctttg cttctcccac  16440 

ctctgcccca cctgtagcca catgaaaaga gtggttctgg aagtccctgg tgtaactttg  16500 

gtgtagcaca tgggctgtgg gctctgtgtg cacactcgag acccagcgca agtcaccact  16560 

gccatggagt cacctgtgga cccaggggct gggctagtca gagcagtaga tgggatgagg  16620 

atctgggggc cttgagtgga ggggcagctc tcagtgagaa gagggtgcct ttggctgcat  16680 

ctgcccctgg aagggagcca ggaaccaacc cctctacagt ggagatgctg atgggtggcc  16740 

tcgtcctgga gaaggggcca ggatggaaag gacggacctc caggaacagc cagcgccctg  16800 

gcttcctgac aggcagctcc caggtgggga gaagggcttg tttgacacag gtgtgaggtt  16860 

tgcagataca gggtgatgag gtggggccag tattcagaat gcagaacctg accctccacc  16920 

atcacggacc atccgtttgt gagcagcaca tgcagctgtg gggccgtgtt ggagcacagg  16980 

gtgggtgtga gtgagcgtgt gagactgtgc gtgagtgtga gtgtgagaat gagtgtgaga  17040 

ctgtgtgagg ctgtctgtga gtgtacaaga ctgagactga atgtgagtgt gacaatgtgt  17100 

gtatcatgaa aaacactgtg agagactgca cgtgtgtgag tgccagtgag tatagtgtaa  17160 

gtatatgaga aagtgtgaga gcatgagtgt gtgtgtctgc ttgtgactgt tgtgtgaatg  17220 

tgggtgagag tgttagtgca agggtgtgtg agtgtaagag tgtgtgagag actaagagtg  17280 

tgaagtatgc aggtgtgtgt gacgtgggtg taagagtgtg tgtgcaaatg catgagtggc  17340 

tgagtctgca tgagtgttat gagaaaatgt gtgtaagaga ccacgtgaga gtgagtgttc  17400 

atacatgtgt ctgcaagtgt gtgggtgtga aaaagtgccg gagactggga gcacatgaga  17460 

gtttgactgt gtgcatgtga gtatgtgggt gtgttcctgt gagagaggtg cggggtgtgt  17520 

gggaggggca gctccagtct ccagggagca ctcctagcgt ggtccattct tcacggacag  17580 

gagcccgttt tgtaacccca ctctgagctt agttcctgct cgctgttgca cccgtgccct  17640 

agggccttcc ttggttcttt cttgcacaca gcagacatag gtgccgtggc ctggcttcca  17700 

ttgccatctc tgccctagac gttgtgcacg ggttaaaggg aggcagcgcc tggtggaacg  17760 

tcctgggctt ggatgtggca ccggagcctt gactggattc tgttccacta ctgggcttcc  17820 

tgggcatcta ccttggacct agcgtggagt ctcacgttca agttgtcttg cctgaagaag  17880 

acagctagtg ggcctgcctt gggtctctgt tgaacaatta aaggagcacc gagatcccct  17940 

ctgttgaata attaaagaag ggagagagag acccctgctg caggacgcct tgcattgtaa  18000 

cctctgggaa gcataagccc tgctcgctat aaatgagaat gtcacttcca catctcctct  18060 

gagcatattg gtccagaaaa ctacctccca cattaatttt catatggcta tcagacatgg  18120 

gagatttatc agagagaagg aaaagtgtaa ggatcaaaca cgtgagtttg ggagaataca  18180 

ggaactaata ctaatgcaaa attagaacgg gatttaggga aattcagtac agcagcacag  18240 

agtactacaa aataaaagaa gctttgttcc tctcgaaggt aatctgtgtg ttgtttccct  18300 

aattttaaaa agtaatacat attactggcg aaaaccctga aagatagaaa catttccgaa  18360 

aaaatatgaa tggtgcctag aattacacaa cccagagaga agctcttatg agcattttag  18420 

gacattttct tagtttttaa aataaaaatg aaaccacact acacatgcat ctttgcccac  18480 

tgtcttttgt cacttaatgt tggagcgtgt ttgtccactt caagttccat aaacttgact  18540 

tttaatgaca acatgaacag cccattttga gtgtggccca ttataacact tactgcctgc  18600 

aactgtgtgc caagccccag cctttgctgc attatctgta ggatccccta agccagcttt  18660 

gtgttgttct tatttcattc tggagatggc tttgaggact cgtcccctgt gagcagagag  18720 

gcagagtcca cccctgccaa gtggcccctg ggctggcctc tgagtgagca tctactgctg  18780 

gtgacaggac atgggttcaa cagcagctcc cgccagcccg gtagcaacgc cttgagcaag  18840 

ctgccctctc tcttcttctc tgaccttccc cgtagccaag gactctcaga tgggaagaac  18900 

ttgaaaactg tccctccttc cttttctcta gactgctgtg cactcagacc ctttggaaat  18960 

gcacccccac caggttctct gctggacccc atgtatttac ttagacactt ggcagatttc  19020 

ctaagactgg gaagaataaa ccattgttaa atctgaaatt cacacgagag acagaagaat  19080 

ttgtgaagcc tttgctggct gccccatcag gacatgtccg ggaggaagag tgccccttcc  19140 

tcagcaggat gagggtagcc atcttgttcc caggggcccc tctgtcacca caggcagtgg  19200 

aagtgggcag tgcctcccag ggctcatggg gcccctgtct gccccgtgta ggctttttgg  19260 

ggtgggaagg gatggaaggg aaggaaaggc accagtgggt aaggaagagt gaccacagag  19320 

gaatagagtt ggcagttgtg gattttaaag tcagatacat gtggtgacaa atcattgctc  19380 

tctgctgaca tgctgtgtgg tgtaggatga gtactcagac ctgagcctcc attctccttg  19440 

tctgcaaaaa agacgtagca ggccgcctta atggagtgat aatgggcttt tctctatgag  19500 

agcacctgcc caggcttaga ctgtcactgt tgctggataa acgttggtct cctgtttttc  19560 

tttcttttgt aactacctcc tgggcagatg tgggtgcatc ctagcacgta gtggttttgc  19620 

agtatcttaa accctgtctc attttgtcct gttttttcct ggcgtttcaa acttctcatt  19680 

tccaaggttt gcagtccgag aggaagggat ctccacaccc cacagaggcc tgagccttgc  19740 

tgaccttgtg tgcctgtgtc ttttcccttt tgggaatgga aagcaggacc ctgcagggct  19800 

gaagccacac tttctgtaca ggccacatcc tggaatccag ggcccggtgg ccctgctttt  19860 

gcaggtgcct tgactccccc attcttcctg cgcttgcaga gcctctttct ggcctcagac  19920 

ccacagctgc tctccgtcgc tgagttccct ccattgtgga aaccatctta ctcctggtgg  19980 

tcccagtggc aggatactga gaagtattga tccatccaga gggagaggca tgtagttctg  20040 

cttaaccaga catggtgcca cacagatttg agcacaagca ccggaggtgg gacagtaaga  20100 

acattttttt tgagactttt tttaaatgaa gattgatttt ttttgagact ttttttaaat  20160 

gaagattgat ttttttttga gactcttttt gaatgaagaa cattgttttt cgttgtaatt  20220 

ctttggggag agagagaatt gaggaacagt ttcaaatcca tgtgttcaac aggaacattt  20280 

ctggggccag ctcacagaat gcctgtgttt cagagcctcc tctggtgtgg gaggcccaga  20340 

acggagccca ctgttggctc tgtgtcagct catgcacaga ttgtattccc tagctgctct  20400 

aaaggagaca tgttgaagga aacttccaag ttgaaaggtt agaagaagtc taagcgtcct  20460 

gcattgagac ttatgtttta gtcctggaaa ttccttttcg gaccctgtta cgacctggtt  20520 

gtgccttcga gtgcagctgc aaggctgtgc tggctgttgt cagctaaccc taatgggacc  20580 

tcagtttctg aagccagtga gtttccaacc tcaggcctga gatcagagtg cgttaacatg  20640 

cacttcccat cctccttctc cagatcaaag agaacacttg accacactgt ccacagtttt  20700 

attattatta ctatttttag ttgagacata ataattgtac atatttatgg ggcacagtgt  20760 

gatattttga taaatgtata caatgtacaa tgctcaaatc ggtgatttgc atagccattt  20820 

tttctgtgtt cttcatgcaa cactgcatgt tggaatgata ctgccatgtc atttttgata  20880 

aaacaccaca tattatcttg catgttgaac agaagtacta ttccctcccc tttgaaaatt  20940 

acctctctag aagtgacctc tgaagttcta ggcagtgagt ggactgtaat gtcagtacag  21000 

ggcagcggag ctcctggtgc tctccaaaga taggtcctcc ctggtggaat gatttccctt  21060 

gaggccagct gcatggctcc tttttccagg aaggggacca ggctctcagt cacttgtctg  21120 

tggccatgac acttcctttc cgtcactaac acccagggct atcgcctgcc accttgactg  21180 

cttcaggaac aaactccacg tctgagctga gtaccaggtg gtgcgtgggg ccagcccaac  21240 

tttgtgacct cacacctctg ctagccctct ttaaactcat tcttggaatg gctgcaaatg  21300 

catgtgtgtg ttgaagagca ctggagtgag ggtggtcccc tccctggcct gcagcacttg  21360 

cgtcctgtgg agggtggtga gtgtgaggat gaggaccact gcaccatggg gatgaggatg  21420 

ctgtagtgag gggctgctgt gtgagtagga ctctcagata tgccatttca tttcatttaa  21480 

tcctccccct tgtgggaggg aaaagagagc aagcattatg ctcattttac ccataaagaa  21540 

atgggggctg aggatgtcct gcagctggtg agggatacac gtgagacccc aaatcccagg  21600 

tcctaacgca cacttcttcc tccttctttc cctggatctg tggagggagc tgctgggaac  21660 

cgaagagagg atggaaggaa gaggtggaag gttgcttgga aggacctgtg tttggatctc  21720 

ccttgcttgg tcgctgttgt gtggtgctga gcagatgtcc catgggacag ggagggtggt  21780 

gtacagcctg gctcagccca ggagcctcct taagcctcac ctgaatggca tctagtagct  21840 

ggtagggtcg ggcagtggag cccccccatg ctgcagacag aaacaagaaa ccttacagcg  21900 

gtcctgctgc tcctctcagg caggcatggt gggttgatgt cttgtcgctc tctgtggaac  21960 

cttctcttta tcatgccgac ctttgcattc ctgtgagctt ctgaagtctc tggatgtagg  22020 

aggtgtcagt ggcatatcat ggactcagca cgactgtatg tcactatcat gatgtatttt  22080 

ggagggtggc catcaaccaa tttggaacaa agtcattcta agaggagcct tatgtgggcc  22140 

actcatgttt atgaatcaaa ctccatcttt cagtgaaatg ctactctgca ctctacactt  22200 

acagggacta tgtatttata gtttaaatct aaactgtagg ggacagtgtt gttgggtttg  22260 

catattcaga ctatgtcatc aatagaaaca ttcctctttt aatagccggc agcaggtttt  22320 

tcctaactgc caaatgataa gaatccctgg gaagaggttt tagaaaatta gatcccagcc  22380 

cgacccccat tttcaccaac acaaaaagaa cagaatttgg tcaagagtgg ggaccccagg  22440 

gatctgtgtc aggaataacc gcctgtggtg tttctggcaa ggaaagattg ggatggtgaa  22500 

tatttattgt tgatgcttga aataataggt tttttccctc tccagaattt ctcattgcta  22560 

agattcaaat tatcatagtc gggccatgct ctgcccaagg tcaccgcagg tgtgtggtcc  22620 

tcagggcact ctggtcctga caggacacca ggggtggcat gtgggggcct ccttcccagc  22680 

tgggtcatcg tcagtcccac ccagcattcc atccgggcac tgtcctttcc cagcactgag  22740 

agtgagtctg ggtgcttggt cctatctcca agtggcctgt tctggaagga gcatgctggc  22800 

ctggggaagc tgcacatttc caaggctgtg gccttgttca tccctgagag tctgagaatg  22860 

ccctgggttt cccatcagct gccttcagca accacagcat cttcccagag cagtggtgac  22920 

caggatgcag catacagcac ctttgagaag cagcaggcaa gatttaagga aggggcgcct  22980 

cactccgcct tgaggaagcg ccctgcagcc tgcttgtctc ccttttaaca ggctcctctg  23040 

ctgaacagcc cctgggcggg agactcagga agctgagcct ggggcagtac gacaacgatg  23100 

ctggggggca gctgcccttc tccaaatgtg catggggaaa ggctggtgtg gactatgccc  23160 

caaacctgcc gccattcccc tcaccagcgg acgtcaaaga ggtatgtgcc acagccaggt  23220 

cccagtttct gggcccattc cactcccttt cttgtcctgg aaccccgagt gaatgggcaa  23280 

tgaccaggcc ttgtccctga atacagccca cattatcctc cgcacccacc ttccgtcctg  23340 

gtttcacaaa tatggtcgtg gctcctctgt acctggcaag cggtgtggct gggagagcac  23400 

agtgtgcagt cagctggcct gggtaatgca ccccagagat agctatgctg gtgaggccac  23460 

ctcactcagg gcactcgagc ctctatgttc taatctgtag aatgggcaca aggagcacag  23520 

catgtgggtg ggttgtgtgg gttcgaggta gggctcttat aggcctggcc ttagccattc  23580 

tccatagccc gacagcagca gccagtggca cacacagcct tccttcaggg tcatcacact  23640 

cacacagggt cctcagtcct ccctccgaga cctccctagg aggtgaccca cagatgaggg  23700 

ccacagatga gagcttcttg ctcttccaag aggcctaggt aaggcttcta gtcagaatgg  23760 

atgtaaagca ggtcggtgta tccaaaacga ttaattattt tagacttggg tgggatttct  23820 

tttcaagttg gcaaagttgg aagctacaga attcacaaga aaaaaaagct attcatagtc  23880 

ttgactcaca aaggaaacca ctgttaatat ttagaatatt tccacccggc cttttttctg  23940 

tgctatgtat ttaaaatact atgtgttttt atgcatctgt gaatatatta ataccatggg  24000 

taaggactgt tttatccagc tttttcgctt aatattgaga tactcattta cctgtaccat  24060 

tacaaactct gtctacttca cttattagct gtatattgta ttagaaggat gggccgtaag  24120 

ataccttccg tttcctttac tgttgaaggt gaaagtgttt tccagttttc catggctagg  24180 

agaggcgggc tggttttgtg cagtggatcc agacctcagc ctccttgtcc tactgtcaga  24240 

ggaggggttt gctcagtggg ccagcctggg ggagccacaa ccacaactgt ttggaggggc  24300 

cttcacttga ctccctgttc tcacattcta ctccctgtgc caatttcaga cgatgacccc  24360 

tggctatccc caggacctcg atattatcga tggcagaatt ttaagtagca aggagtccat  24420 

gtgttcaact ccagcatttc ctgtgtctcc agagacaccg tatggtaaga atgaagtaac  24480 

actagctgca tgtgctgctc catgcccaag gagggtgaca acagcccctt gctctgcttt  24540 

cttttccagt gaaaacagcg ctgcgccatc ctccgttcag cccacctgag cccccgctga  24600 

gcagcccagc cagtcagcac aaaggaggac gtggtaagaa atctacccgc gggtcacagg  24660 

cgcgcggcac tcaggcgctg catcgcgggg tcgccatttt tacagagaag aactcgtatg  24720 

cagaaatgtt tccatttgtg tcgtatctca gaagccttgg atgaggatgg atcttgctgg  24780 

gaaagatgta gggatgtggc cgtgaaatcc actgtgtggt ggcaacctgg ccttgcatcg  24840 

ctgcctggca tcctgtgggg aaccctcctg taatatgcag ttgatgggac catcagtggt  24900 

gactgtcggg cagcttagca ttggtgcttt tgaagaaacg agaatgccca ccccacactt  24960 

cacgttctct gtggggattg tgccgcacgg gcgccccagc tctgccaccc cagctgcctt  25020 

ctcacacgta ccttgtggcc cctcctgtct gttattagtg ggtgcctaat cactgtccct  25080 

ggatctctgc aggaactcag gggctctgtc catggcctga tcgcgtccgt ctgtctgcat  25140 

agctggctca ggcgagagag tgttagtggg cggtgtttag ggcgagttac tgtgcacttc  25200 

ttctgggtgg acttgaggac ttgcctgaga gtccaggaca aggccgagct caggcaggtg  25260 

gagagagaat gtaaacctaa agctcgtgca catttcaaaa tcactcttct ctgggagttt  25320 

cgttcattac gctgctgctt ttttgcccta gtgaaggctg ctgttaatgg ttattaggca  25380 

cgttacctga gactgagact ttcattaact tgtattttca tctacccctt acccaggagt  25440 

gttgtgatca tgacagctag ctccattctc tctctttctc catagtaaac caagcctgtg  25500 

gactatgtaa tagaaagaca tccttctcct aaaattccct ttatggtttc aggaccataa  25560 

attgctctct tcatatgtag catatagcag ttatactgcc tgtatttctc agtaagtgct  25620 

actgaaattt aaaataagct gcattttaat gtctacatta tgtgagcatt acatgagaag  25680 

tgtgtatgtt ccaatatgca ttagcatgat ggactcacac ataggtagcc atgcatctgt  25740 

tctatatttt ttatcatttc aatagatgca gaaagaggga tgtcccttcc accccatgta  25800 

acccctcctc ctcatggagg tgactgtact tggctcctag cttgaaagtg ttcagtgggt  25860 

ttgggctggc atctagccct ctggcctgga atcctgtctt ctcctgcaac accaaaaccg  25920 

ggtttgtttg aaataggtag atgacaaaca gtggaaggtg ggtaataagc ctgaggaaat  25980 

aaaatactag aaacagcctg caaactcatt aacagctcct gagggaggcc tctaagatca  26040 

ctgtattgag cataagagaa tgtggagccc cgtctaaact ccagaagggt ctaggaggct  26100 

gcaggaagcc tgggtgctca gcgtggggta cccagtggcc tggctgtctt atgctggccc  26160 

gattgtccca gcctggagat gagctccatg tcctgtgcgt ggatgagcgc tgcactatgt  26220 

gtggatgagg atggctctgc acaccagcat gtgttagatt ccagtggctt caacttgtcc  26280 

tgagtactat ctgcatgtac atattcacac agaagaagtc agggctttgc ctttaaatat  26340 

aaaaaggtga catgataaca atattaatgt gagccttcta gatttttatt tcagcagtcc  26400 

ccagggaggg tcaacttcac attagcccac aaggagcaca gagataacac agtgctgact  26460 

tagtggatgc tttcatcaga cagtgtggtg agccagtgcc cttgccagga ggccccaccc  26520 

actctgcaaa gtcaagtgga gttgtgagac tcctccaagg gcacagtaat aacagaggta  26580 

gctcgcccat acagaatgtg tcccctgatc tttatgattt ccttccattt cacagtcaca  26640 

ttctatgggt cactcttact gttaccccca ttttacaggc aaggaaattg acacgaagaa  26700 

gttgagtagc tagtaagtgg caaagtcaga gtttcagctc catcagccga ctccacagcc  26760 

atgggcagat tatacagggc tgatgtttca ctttgtcttg tctaacctag aagtgaccta  26820 

atgtcacaac taaaaagcac atggaaagtc tcacagtcat ggaataacca tgtaatttgt  26880 

acatttaggt aacccctatg aacctccacc tccttatcta aaaatgcaga ctatagtacc  26940 

tgccattcac agccactgtg cagttttgaa gtagtaggct ttaggcatct gcagtaatgc  27000 

ttaactgcgt atcatttagg cctagatact gatgtgcata taaatgacag tatttgcttt  27060 

aaaataccat tagggagagg cttcacttcc cggagggtga attagacata cttttctcta  27120 

tttctcctgc taagtacaac ttaaaacctt ggacagtaag tataagacaa atataagaaa  27180 

gctctgaaag atggggagaa ataggccagc tagccatgga cttcagggcc aagggacccg  27240 

gtaggcctta tttataatat ctatgggcca ggaaacaatc ttcagaggac taaaagtaac  27300 

tgaaccatgc agaacatgtt ctccaaccac aatggactca ctagaaatca gtaacagaag  27360 

ggcaacagga acaccttcaa cacttggaaa ctgaacagca cacttataaa taatctatgg  27420 

gtcaaagaag aggtctcgag ggaaatccaa aaacatactg aactgaatga aaatgaggat  27480 

aaaatatcaa aaattgtgag acatggcttt atccactgct ttaatacagc cgcactgaga  27540 

ggaaattttg ggcaagaaga aaattctgaa atgaatagtt tatgctctta cctccataac  27600 

ctagaaaaag gagaacaaac tagacccaag gcaagcagaa ggaaggagat aataaaaatc  27660 

taagcagaaa tttaaaaaga tacagagaag taatagagaa aataaatgaa agaagtggtt  27720 

ctttgaaaag atcaataaaa ttgacaaacc tctagcaaga ctaacaaaaa aatggaggac  27780 

atagattact attgttagga aggaaacagg caccatcact aaagaccctg cagacaccaa  27840 

aagaataatg aaggaataca caaactactc tacatgcata gtttttaaaa cttaggttaa  27900 

atagaccagt tccttaatga gcatgaactg tcacaactca cccaatagga aatagactac  27960 

ttgaataccc tgtaactata aggaaattga cctagtaatt tataatctcc caaaaaagaa  28020 

atcttcaggt ttcactggat aattctacca aacatgtaaa gaagaattaa cactgattct  28080 

acgcaatacc ttccagaaaa cagaagaggg gggatcatgt cctaattcat tttgtgaagc  28140 

tagtattacc ctgataccaa aaccaggcaa aaagaacaga aaaagaaaac tacagaccaa  28200 

tatccctcgc agattcagat acaaaactcc ttaacaaaac ataaacaaat agaacacagc  28260 

aatatataaa aagattgaca cactgtagcc aaatgggaca tattctgaga tgcaaggctg  28320 

gtttagtatt tgaaaattca ttcatgtaat acactatact aacaggctaa agaaaaagct  28380 

cacgactata tcagtcaatc caaaaaaaga ataaaaagag tttggcaaaa ttcacatcat  28440 

tcatgactca aaacttccag caaaatagaa gacaggtact ccttcaacct tacaaaaagc  28500 

atctaaaaag ccccacagct gacagcactc tttttcaaca tagttctgga agttctacag  28560 

agacataata caagaaaagg aaattaagac aacagatgag aggaaagaaa taaaactgtc  28620 

cctttttgct ggtgacatga tcatctacgt agaaagcccc agggaatctt gagtctgctg  28680 

ctgacatgat tgtccaaaca gaaaatccca gggaagaggc ggagcttgca gtgagctgag  28740 

attgcaccac tgcactccag cctgggcgac agtgtgagac tctgtctcaa aaaaaaaaaa  28800 

aagaaaaaaa agaaaatccc agggaacaac aaaacaacaa caaaaagtga aactgttaga  28860 

acaaattcag ccactttgca ggattctagt tcgacacaca aaaactagtt ctatttcagt  28920 

acgctagcaa tgcacctgta gaagctgaaa ttaaaaatat aagtcacagc ccggcggagt  28980 

agctcacgcc tgtaatccca gcactttggg aggcaggggt gggcagatca cgaggtcaag  29040 

agatcgagac catcctggcc aacatggtga aactctgtct gtactcaaaa tacaaaaatt  29100 

agttgggcgt ggcagtgcgt gcctgtaatc ccggctattc aggaggctga ggcaggagaa  29160 

tcacttgaac ccaggaggtg gaggttacag tgagctgtga ttgcaccact gcattccagc  29220 

ctggcgacga gctagactcc gtctcaaaaa aaaaaaaaaa aaaaaaaaaa aatatatata  29280 

tatatatata tatatgtata tgcacacaca catatattcg tatgtatata tatacacaca  29340 

tatacacata tgtatacata tatttatgaa aaggacatag aggtggcata tgatcgcata  29400 

tgtatacata tatatatata tatatatata tgccacttat aatagctcaa aaaaattaaa  29460 

tggttagatg taaacctagc aaaccatgca caagacttct gtgctgaaaa ctgcacaatg  29520 

ctgatgaagg aaaccacaga atatttcaat aagtggggag acatactgtt ttcatggatg  29580 

gaaaactcaa cctagtagag ctgtcacttc tttccagatt gacagacagt tttaccacaa  29640 

ttcctatcaa aatctcagca agattttttt gtagatatag acaacataat tctaaaattt  29700 

atgtggaaag gctaaggaac cagaatagcc aaaacaactt tgagaaagaa ttaagtggaa  29760 

ggaatgaggt tacctaattt caagacttat tgtatagcta cagtcatcaa gactgtggtg  29820 

tggatggagg aacagacact taggttcatg aaacagagta gagaacccag aaacaggcct  29880 

acacagatat gcccagctga tttttttgac aaaggtacag aagcaagtcg gggaaggtca  29940 

gcctttcaac aaatgatgcg ggggcacctg ggcacccaca ggcaaaacaa tgaacagcca  30000 

ccaaaggctc acactttata caaaaattaa cttaaaatgg atgatggact taaatgtaaa  30060 

atgtaaaaca tagtattttt taaaatggga gaaaatcttt gggatcacta ggcaaagagt  30120 

tatgaggtta ggacaaaagc atgaaccata aaaggaaaag ttgacaaatt agactttata  30180 

aaaattaaac atttttgcta tggaaagaac ctgtgaagag gataaaaaag acaaactgca  30240 

gagtaggaga aaaggtttgc aaaccacatg tccaaaaaaa ggaatatcat ctagaatgta  30300 

tataatctct caatactcag cagtaaagaa caaacaattc acttagaaaa tgagccaaac  30360 

tattattaaa aagtcgaaaa acaacagatg ctggcaaagc tgcagagaaa aagaacatgt  30420 

atacactgtt ggagggaatg tgaattagtt aagccactgt ggaaagtagt ttaaagattt  30480 

ctcaaagaac tgaaaacaga actgccattt gacccagcag tcccattacc ggatatacac  30540 

ccaaaagaaa aaaaatcatt ctaccaaaaa gacgcatgca cttgtatgtt tatcacagca  30600 

caattcacaa tagcaaagac ctggactcaa cctaggtgcc catcaacagt gaattggata  30660 

aagaaaatgt gggacatata caccatcgaa gtactccgca gacgtaaaaa aagaaccaaa  30720 

tcatgtcctt tgcaacaaca tggatgcagc tgtaggccat tgtcctaagc aaattcagta  30780 

tcccctgaat ttaaaataaa agttgaaatt aaaaagaaaa gccactgact aaattaaata  30840 

aatggatttt tattcagtag gaaaaaaaat tagaaaatgg ttcaaagaaa aaaagagaca  30900 

tgtcactgaa gaggacgtag aggtggctta tgagcacgtg aaaagatgct caacatcatt  30960 

agccattagc aaaatataaa tttaaatcac acctatcaga atggctaaaa taaaaaatag  31020 

tgacaacatc caatactggt gagcatgtgg aaaaactaga ccccttatac gttgctggag  31080 

ggattgttaa aatggtacag ctgctgtgga aaacaatttt ggcaatttct taaaaatgaa  31140 

aaacctacat ctgccatgtg actcagtgat tgcattcctg ggcatttatc ccaaagaaat  31200 

agacttatgt tcacataaaa cctgtacagg aactcttttt actttaatag ccccaaactg  31260 

tagatgtcct tcaacaggcc agtggttaaa caaattgtag tacctcaata ccatggaaca  31320 

cttctcagca ataaaaataa gtgaattatt catacacaca acaacccgga tgggtctcta  31380 

gaacattagg ttgagtgaga aaagtcaaaa cctgaagtct gtatagtgta tgattccata  31440 

tatgtcacac tttttacatg gcaaaattgt agacacagag aagagattca tgtctgctaa  31500 

tggttgggag gggcaagagt agaaggggaa tggagtagcc aaaaaggcaa caggagattg  31560 

gcagaagagt ggtggagtaa gaggtcggga aggtggagcc aggccaggag ccgttctctg  31620 

tagttcccag aaggtggtgg tgtggcatcc acatgcaatg tgaggtcatt actgaacctc  31680 

aggatgggga ggtgactgct cagatttgca ttttcacaca tcactgtggc tgctgcatga  31740 

agaacacggt gggatggaca gtgggctgga acagaccaaa tggtttcaga agagatagga  31800 

ggaaatcaga acatttgtgt aggattcagg tggtgcaatc agctgacctt aacacagtgg  31860 

aattggagcc tgactgctct ttctaattgt attgcttttg tcattattgt ttaaattagg  31920 

ttctggcttc ttgttaatta gtatgcagtt agtataacac tatctccata aaattcctct  31980 

gcagatcgca ttactaaaac ataacttgat acctccttag tcagcataag ccccatgtgt  32040 

taagttcttt tccagacaac caccaggata ggtgtccaag agaaatagcc cagttagtta  32100 

aaggctgtaa ggacagattt tattcaggat tattgcaaca ggagaaagtg ctgggctcag  32160 

ccccaaatgc agcaaagaca gctggagatt tatgaccgag gaatagagca aaaggatctg  32220 

gtggatggaa agtcattaag aagggacatc aagggtaggg gggttcttgc taaactggcc  32280 

taacacggtt tctgctacag acaggccagg gacttagaca caaatggcga gggatgagga  32340 

gcttgatgac gtgtcaaggg ggattagata tcaagtgtgg gggatgaaaa gcaggattct  32400 

tgctggaact gagcttgcca cggttggacg tggaaggcca atgttgaggc ctagtggaga  32460 

agagggcttg gaggagcctg gctaaggttt ggtcaaggag agtctgtcac aagatagacc  32520 

catctgtatc caggctaacg caatagggtg accaaatgca gcccgcacgc ttctctgtgt  32580 

ttctctccag gtcctttggg cacttagttt ataatttttt attttctatt ttttattttt  32640 

atgggtacat agtataggtg tgtatggagt acatgagatg ttttgataca ggcatgcaat  32700 

gtgtaataat cacatcatgg aaaacagggt attatgggca cttagtttag ccataaggct  32760 

tccgtgccaa gtggcctggg agccagctgg ggccagcttc tgccacaggc atccttcacc  32820 

cacccttctc acaaacaagc gattcttcaa taaacaataa acagaataca caaaaagcaa  32880 

accaaaacat ctctagattt attaatagat gggtgaatta aaggagtctt ttccaaataa  32940 

tgtgactaac agaagccaag ggggatgaat gcccaaagct ggggcttgcc agaacctgct  33000 

ggtaccgaga gctgattgct gaagtgtgag gaattttgtg agccagctga cagcacattg  33060 

gcagcttggg atctgccagg gcgggattgt ttacaccaca ggatttagca aacgttatga  33120 

atcaacccct ccatcggccc caagcttccc tgacacacca aacagtagaa attcactgcc  33180 

tttttttttt ttttttttaa ctctgcttgg tgttagctaa ctagtcatga agaatagagg  33240 

ctgaagtgac caaagagatc tttctgcatt ttgacattca aatatttgga aagattttcc  33300 

gcattcagca tttggattct agtcccattg ccaggctcaa gtaagctctg tgataacaac  33360 

actcagctgt tggaaactgc tgtccgaagc atctctcagc agatagggag gcctaaaagg  33420 

acacggcaga gtggtgtctg gtgggtcctc tcctgacatt tcttctctct ctggtcaaat  33480 

gctggatgca cacatatagt ggctctgaga cttcctatct gggtgagctc aggcagttct  33540 

agggacctct ctgagcccta gtttcatgtc ctgtacaaca gtagtcattc ctactgcaca  33600 

tggttcttga gaagattgga ccagaacatg tagctctggc tcctggccca gacctgatca  33660 

acactcagca aatagtggac actgatgctg ttaggagaac agagcatcca tatgaagggc  33720 

ggttccctga gctggggaga ccagtgacaa ctgtaagtct gggttcagag catgagtcgg  33780 

gggacggaga aggcccctgg gcatctggcc ctgggtggct gagccctggg aatcctgctt  33840 

ttcccagaga tgtgcttgtg cccagtgtgc tcatgtttta aatgccagca cctactccag  33900 

gaaaatgatg ggtatttcaa tatctgctca cattatgcat atttaaatat gaatttaaat  33960 

actgtttaat tctcctaggg atgtgttgtc atttaaaaga ggttgtgatt agcatgaagg  34020 

actggggaca ggagcaggag atggcagagc agctgtaggc actgatgtaa tgcctccagc  34080 

tttatgagga cgggcccaac caggcttcac ccatttgggg ccctcaagcg ggagcgtcag  34140 

tggcagccct cgccatcgtc cgtctgttga atgtattgcc acatggccac attatgcccc  34200 

aggagccatg tgttggagga cagtatcctt aggcttctca gaaattccac atgggagcct  34260 

caaatggaca tgcttttctt gaaaacaaaa atatttgtaa aaatgtaaca atgggagtcg  34320 

tttaatctca agtctcccct ataagcaaaa atagataaaa ttatgaaatg taagatgtaa  34380 

attattctgt ttcttagctg atccttaatc ttgatgatat tttcaaaaca aatgaataat  34440 

aaagacatga gaaaaggttt cctttaaaaa gtcgtggttc tcgccaggcg cagtggctca  34500 

tgcctgtaat cccagcacct taggaggcca aggcaggcgg atcatgaggt caagagatag  34560 

agaccatcct ggccaacatg gtgaaaccct gtctctacta aaaatgcaag aattagctgg  34620 

gcatggtggc gcatgcctgt agttccagct actcgggagg ctgaggcagg atttaaatac  34680 

tgtttgaacc caggaggcgg aggttgcatg agccgagatc gcaccactgt actgcagcct  34740 

gacaacagag tgagactctg tcaaaaaaaa aaaaaaaaaa aagagtcgtg gttctgatac  34800 

atctcagctt ccaaactatt tcataatttt ttaaaaatat aaacacataa cataaaagca  34860 

tctatttgaa ggtgaacatt gcaccagcat tcagtagatt tacggagtca tgagaccatc  34920 

gcccctaggt agttccagag catccttatc ctataacagc tttacaagtg gtattcagag  34980 

ggggtttggg gactttaggc ttcagtgaaa aagattagca gttaatgtta gtttacttca  35040 

agaggatgcc tttatatatt ttgcaacttc tattttgtgt tcagttcttc tggagagtag  35100 

ggtgtaggca ttttaggggc ctggcttcca agcatgcagc ctcttctctg ctgtcgattg  35160 

gaggttttgt gaagggctgg gaggattgcc tccatccaag tgccagtgca tgagactgat  35220 

caggagtggt agcatgtgaa gtggtcctca ttggctcaca agaggggaca caggggtttg  35280 

gttggtgctg tgcggacttc ctggatttgg taggtttcaa agggtcatga tgtttgccac  35340 

agggaggaag aaaagggcag taccagtggc actggtcctt accctctgta gctctatgat  35400 

cttgaacagt ttgcataacc tctggaagca tcatttaaat ctaagcaaaa taagaatgtg  35460 

tgtgccatgc atggtattgg gggcagtctt aaaaatgaag atttcagcct atgaatatgc  35520 

tagtgtaaca aaaatttgtc ttaaaattta gttttttaat tcagaatgca ctttcttatt  35580 

gaaatagttt cagagcccca gggactgata gagagacaca gcgtgagaag aggacaagag  35640 

gaagacagag acagagagat tattttgaca caatgcttta tttttattga aaaagctgtc  35700 

atccttcaaa aattgacaga tacaatgctt ttaccaatct tcttctttct ttcctgtact  35760 

cgactccctt ttctgttgaa tttttatgag ctctgaatga gaatgtttat aatagggaca  35820 

aaggcatgta ctgaatgtga atatgtgtga catttataga ggcccttgtt tactttggat  35880 

tttctagagc ctcaaaagca catgcattcc tatatggatt tctccatggg tttatattca  35940 

ggtacgtagg catatgtaag tgtgcatagg aatagacatg cctggataca tgcctgtgat  36000 

gtactttgca ttccaattag tgccaaagaa tgcacactgg tgcatggtga ccccaaaaaa  36060 

ctggtgtgga ttagcaaaca tcgcagcctc ctccaacccc tgccccagat gaacaacatg  36120 

aaaaagaaaa gttgactgct tctaaattat atttaaaagt aaacatcagt gctgggttcg  36180 

tggaggtcag cctaaagtgc tggcctgtga atgtgccttt aggggtcttt tgagatgaga  36240 

acatgaattc atttgagggt gatgaagcta aaaaaaaaaa aggtgttggc tttctgtgct  36300 

gacacctcat ccgcggagca ggccagcttg gaagtgtccc catgtcagcc tgcagacttc  36360 

tctaccatgc tgaatgttct cgtttgctca ctttgggttt agaggaatct gcttttctaa  36420 

atttatttat cagctcattc cattaccccc tcctctcctg gtggactgtt cttgaccctc  36480 

agcatgtaga agttattctg aagtgctgct aacaggattt gatgctggcc ctggggcttg  36540 

gtgacagatg tggctctggt cctgcccgtc tgtagctctg tgatcttgaa cagtttgcat  36600 

aacctctgaa agcatctttt aaatctaagt aaaataagaa tatgtgtgcc atgcatggtg  36660 

ttgggggaag tctcttaaaa atgaaaattt cagcctgtga atacggtagt gtaacaaaaa  36720 

tttgtcttaa aatttcattt tttaaattca aaatgcactt ccttattcaa gcattttctg  36780 

agccccattg tctatgagaa ttgtgctcca tcccgggatt gaggaaggga ggcggtcctg  36840 

gccctggggc agctcgcggg ctggggtccc ttctgaagca gcctgtggct ggtgtggaat  36900 

ccggaatcca cagctcgggc ctgagcctgg gcttgtctcc tcctcgctgc tttgaacagg  36960 

aaaaggcagt tcagcccagc aggatgcctc ttagaactgg gaatggcttg gaagaaaatg  37020 

cttatgaagc cccagcatat aaaatgtgca aggatgtttc cctgctggaa gcatttacct  37080 

ggtatccctt gcatttttac tttcctccga aggccctcac cttgtaatcc acctccccac  37140 

agttccatcc cctctagaca gcagcctgcc tcacagtggt gtcccaagag cactgggcgt  37200 

caagaggtaa aatgcctggg cattttctct gaagcacctg ttaccactgt cccttcaggc  37260 

tgtgattcct ggccaaaatg cacccattct ttttgacaca cttgggaggg tctgggattg  37320 

tgagacttgc agaagggtca gatgtcttga gtcactgaga gggctgaaga aggaatatgt  37380 

agtctgcttc ttgacatttg ttactggccc gggcctgccc catcagagcc tttgagggca  37440 

ttaccaaggt gccccccaga ttagtgtacc tcctcaacag ataggcattg gccaggctgt  37500 

cctacttagg ccaggaacca ccttgttgtc tgtttaaatt ctatcacatt ttagtgacac  37560 

acatatgtag acatgttata tggtacatat gtgtgttatg tgtgcaggta tttatggctc  37620 

tgcctagatt gaggcatttg ccactttctg agcacttctt acaggccatg cacttatata  37680 

tgcacacatg tagagaaaga gcaaatgaac aagtttacaa aaaatcctga aagccaggca  37740 

agtgagaatt ccatcatttg gaatgaaagt aaacttttct gatgcttcag ggccaaccaa  37800 

gtgtgcgatg ggcgtcagag gtcaggtctc catgtgtcac ctggcagagg gatggtgtga  37860 

gcagctcact ggaatttgat ttttccagag gagcatgaga ttgggttact gtgaagtccc  37920 

agtgtcgctg aggttgtgga gggtttgtgt tttgtgtttg tttttaattc cttctccgca  37980 

atgcccaagt gagcactcca cttgagtctc aagaacccca gagtagagct cgccctgggg  38040 

tgctggccag cacgtaattc tcaggaacaa acaagtacat tcgaataaag ctgaggatct  38100 

cagtctgcag tgcctggtcc ctcggaggca ttctagtatc cctcttagtt ttgttttatt  38160 

ggggcagagc ctgttgctga aaacagaacc tgtgggtcac cctgactatc cttcccaggc  38220 

cttcgagaac tgccttgcat gtagtagaga gactcacagt ttgcaggagt ggcaccgtct  38280 

ttgaggcagc tttcacataa agcatctgaa gttcctttgc taagtcatgt gcccagtcct  38340 

caaaggtacc tgcagatcac ctgatcgctg ggagtagggc tggtccaggg ttcctcttat  38400 

tgtgtgcaca cataaggttc gcccgagtcc ggtgggacag agatgtggga ggtgatggga  38460 

tgcagcccct gtaggacccg tgaggctggt ggacaggcag tgcgggctgg tgggagggtg  38520 

ttaagggaga attccatcca gctgatcagg tcgtgtctca ggaaggacgt gccccctatg  38580 

gaggctgcga gacctttaaa cttgctcatc ccttcccgtg tgtcttctct gggcgcccca  38640 

gctcctccct tctccttggt ttaatgcccc ttttctcacc tccctctggc aaccaagtct  38700 

gcttgtgtct tcctccgaaa gggaaactcc tgttgcccct tctctccctc tgttcctcct  38760 

ctccctcctt gcttcacctt ccctccgtcc ttttgtttct gctgcctcgc tctcacctgc  38820 

atttgaagga tgtgacttcc cagtgggacc tgggttggga tttggtgtca ccctccctcc  38880 

ctcagcctca ggacatttcc agagcagagt cttcatcaca ctcctggcat ctaacacaga  38940 

gaaggatctg gataaaagtt tgttttgttt tctgatgggt aagtggaagg agagagacag  39000 

tctctcagct ccagggagct gagtgcatca tgcctgcaaa gggcctgagc ccgcagagtg  39060 

ggagctgcgt gagaccagca cctgtgtttc tgagaggaga cctggcattg ccggctggtg  39120 

gggtgggctg tcctcttcca ggtgtctgat ttgcacccct gcttgatttt gctaaggtgc  39180 

agtgggtggt cctggctgta gcagagtcaa catgtggaca gtccaggtcc tgtcgtcccc  39240 

ggggatctct gggtgtttgg gtggggggag cagactgtcc gggaagaatt tttaaatgtt  39300 

ttttcctcag tggacttgct gccacctgga gcccaccttt gaaatcactt tagtccctgg  39360 

cactgcagct gaggagaaag aagcaagaga ggaaagataa acagatctcc agaagatgct  39420 

taaatctgta gattcacact caggattgtc ccagtcatgg ctgtgacacg ggcacagaag  39480 

cagcatgccc tgcctcctcc tccctgctgc ccatccctgt gggtttgctc cgagtcactg  39540 

agcccacagt tccacggagg gaatgggacc cacccttggg agtgccatcc tggtcacagt  39600 

cacccttcct gggcctggct gccccatgct ggtgccgccc cgtgccgcct tcctctctgc  39660 

ttggggagtg acaggcacgg gaaaggccag tccatccgct tccgctgagc ctgctctgtc  39720 

cgtggtcagg catttccgac agcatcattt gcaggagctg ctgctctgca acacataaac  39780 

aaccagggag gaaatgccta ctcagacctt tgggaggaag gtcccaggga tcttcctggc  39840 

ccatgtgcgg agcggtggcc ctgagggtcc caggcaagcc gtgtccctct tggggtaggg  39900 

cattgacctg cccactcttc acaggttgat gagtgtgcca gggtcgtgca ggggctggac  39960 

cggccaatgg ctcggctcag gctgggcagc aagctgtgct ggaagcacag gcgtgcacag  40020 

gggctgtaag aaaggaggca gcccaggagg aacggggacc tgctcttcca gggagagctt  40080 

tctaggggaa ggggtgacac accagcattt gaagagggag tgggattttg ccagacacaa  40140 

gagacaagag aagccaggag tgagtgtctg ttctgtgctt ccccttgtga aaaccctgag  40200 

taatgtaccg tgtctctaag gcccagacac atgacaggcc cctatgttct gccatgtgga  40260 

ctgggttata gtcagatttc gggtcacggg aacagagcac tttgacttga ctgagggaga  40320 

tggtgttcca aatgctgaaa aaaatgtggg gtcacttgaa aagggctttg tagaatgtat  40380 

aggagttttt cagcagttgg cttaggagtt tggcctttta gatgagagaa gcatatgagc  40440 

aaagaacatg gaagaaaggg gacacagtgc gtagaggctg ccaacagcct acagtaggtg  40500 

ccagccaggc agaacaggct gagggatcca gaatcaggct ctaggacagg gtttgggcag  40560 

gatgttatag cccattgggg cccggaagaa aacctgcagg gtttgagcag tgcagtgaca  40620 

gggtgggatt tgcattggaa ggtcccctgg gctgccttga ggagtgaaag gcttccagcc  40680 

tggtggccag gccagatgag aggcagatgg ccccatccag aggaaaggga catgggtgta  40740 

ggctcctgcc ggggtggggg gcagaggact gactagggac atccttgttg ttagagactg  40800 

ttcaggcttc cacttcctct ctggctagtt gctggaagcc tctctctgct gtgagtgtgg  40860 

ggtcccaggg gaatgggggt ttgattttgg aggggcaggt ttgggggcat ggtgggcagg  40920 

tcctgccgct tgtgccttgg gtgatggctg gcctgaggct gaaactaagc ctggttgggt  40980 

ttcagcaggg aggttgcaag aaattaaagt tgggggagga aaaagtgaaa agaaatgaaa  41040 

aggaagcaaa ccgcagcagt gagcaaggcg gggccagggc cgtctggagg cactgactgg  41100 

gcaggccgcc cgcgacagcc agcagcagct caacaatccc gggattcttt cccgggcctg  41160 

agctctctcg gccgccctct gaatgggcct ctttggaggt ggccgccccg ccccctgcac  41220 

gactccctcg ggacaggccg gaacacagag ccctgcctgg gtgggtgggg gacgccaccg  41280 

ctgggacagg gactcgggac tctgctcacc acgtagggct gctggggaca cagcccaagg  41340 

agttccctct gtctggccca catcctccca ggcccttcca tggactgacc agggtcctgg  41400 

gtgccaggta agctgtacat tgggactcat tgcttcttcc tgctcagtcc ctacacgcct  41460 

ggtgtcttct gtgctcctgg cgcctctggc ccggatccag ttgcccttgc tgaaacttga  41520 

tctcctgggc tccagtggag gggggtgggg aggggtatga ggtgggatgc agaggtcact  41580 

gggccaggaa tcctgggcag gacttgggag gagggctgat tgttccaaga gtccccttgt  41640 

cacttgatga cagttctcaa gtcgccaagg ctttgggaca aaacgcccca gcccttgagc  41700 

ctggagggct agtccttcca gaagaaagtc atgctttgtc tttgctgaga ttcactcagg  41760 

gctaacaaaa gcctggttta cagatgtgca gcttttctgg aacaggactg cttcctagca  41820 

cagtgcattc ctttactgaa actgataaag cgagcctgcc ccattccagg gctgtcaccg  41880 

cccccacccc agttccaggg cccttgaggg atcccgggca gcgggcagca ggaccttcag  41940 

aggaccagaa ggctgcactt ctgagcaccc agcacagttg tttctactaa atgccgaaag  42000 

caagcgttag gatcaggcgc tgggttctaa aatgagattt actgttgtct cttctgtggt  42060 

tgaagcaagc aaagagagta tttctaaacg agttcatgtc attgaaaaaa acaaaaacaa  42120 

aaacccatgc attcactgaa agaacctgct cagattatgt taacagagct tctggaccta  42180 

ggggctttgt ttcttcactg tcccttccct cccaaatgtc tgaactgggg ctggggctct  42240 

gtgggaccct gggagagtca gccaggcact gggggtagca cgggcagggc tggcgcctgg  42300 

gcccagggtg ggcctcctgg gcatctgctc cctcctctgc gtggctggcc tgtgattctg  42360 

ctggccctgc agccgacaca gcgtgtgtgt gtgtattcca gctggaagga tggggaagat  42420 

taagagggag cgaggggaaa acccagagct ctttattgtg aaacgagcac tgcagccgct  42480 

ctgagacaag cccaagtggc tcaaggtcca gcttctcctt cccaggctga aaatcttgcc  42540 

cagtatccct tccaggattg atggattgct ctccagctga tggaagatgc tatcttttca  42600 

aaagtttcct gtccttttaa tgtattttat atacattagt aatttttcat gaattccata  42660 

tgcgtgtcag tgtattagag attgtctggt taggacggac atagttttct gactttggag  42720 

gtgagattaa aagaattttg gtccacctat ttcgagagag gggtgatttt ctcccttggc  42780 

caacctgtag ccatggtggc ccgtggggag cctggtgctg tcttctgctg gggcttcctg  42840 

cactctaagg gggaacctca gtgacagggc tctaagttgc tcccagagta cctgtgcctt  42900 

cctaatcccc agggcaaacc tgtgcagaag gttccttgtc ctcctgtagg ggcagagtaa  42960 

ttgtattaca ttctgcgttc tgactcagac cctgctggtg ggaggcaggg atgtcttgtg  43020 

gaaagaacat agttttctga gtccaacaga tgagttggct tcctttgaat aagcttctta  43080 

acctcacttt tcagaatctg tttcctcatc cataagatga tttgcatgtg gaaatgtttg  43140 

tatgaggatt aaatcagata acacctatgt gtgggttagc agagtgcctg gtgtatagta  43200 

ggcactcaga gaaagggagc tgtaattctg atttccattt tactttcttt atatgaaaag  43260 

ttgatatgtg tcatataaac aggattttac aacagtccca agagctgtgt gatttaaaag  43320 

ctgttgacat tcagattggc acctgtactg atggcaacat ttctccaaaa gcacagtgaa  43380 

agctcccgtg gttggagctg ggatctgata atccgcatgg ttctaaaaag gcagtttgca  43440 

gccaggacca tgcatcaaca tagttctaac tgctgcgcac tttgaccttc tctcctctac  43500 

ccttctgttt ccacttccct gtctttaaaa aaaataacat ccaaggcaat caagctgcct  43560 

agttgatgta ggatcaggac aggaagcctg gtgggtgtga tgcatggaag gtggtcttac  43620 

tgctgtcaga cacaggtctg ggatggctcg aagtcctgtg gtctgatgag aataccatgc  43680 

ccattttgtt tacattaggc tcacctgaga caggtggcct ctccctccta tcaggaggga  43740 

ctgtaaacag aatgagttta cagtaagagt caagggacca gaaggtcccc gtcacacagc  43800 

acactctgcc ttcttgctcc gtcccattgc tcactgtgat tttaccagga gataacctaa  43860 

gaacgcagga ctaagaaatc actggaatgt caacttctcg ttccaccacg agatagcaga  43920 

gtggcctgtg gccttccttg agcagtgttc tctgtggaca tatgattctt gattagcctc  43980 

aggtagaatg gatagctggg tggagaaggc aggtgggtac cgggtcaccc aagtaaatta  44040 

aagttaaaca gggttttaca aacgtggagt ggaagataga ggaatgaggg ctcagctggc  44100 

aggaggacga gggtcaccag tgggatgcct ggctttcttg agtgaccaag tacagataga  44160 

aaagcttcta gaatgctatg gaactcattt actgctctgt ggaggtaaga aggaaatggg  44220 

accaaagata aggcttgctt ctggaagatg tgggtcttgg gaacccctct ttgtgcatct  44280 

gttgatggga gtaatggata cacaaaacca cacggtccat catgcttcca agctgactcc  44340 

tccaagtctg gtttcccttg atagttttcc cagtggtccc atcacttctg ctgcctacta  44400 

gatttatcat cacgagaaaa gtcccagttt cctttgtagc tcatgctgca cttgactgga  44460 

ggaaatcaag tcaaggatat cttggtgaca attgaaggga tacaggaatt atacagttat  44520 

gcgcagacta tttaaaaaga cactattttt ttcttaacag ggacattttt caaagttttt  44580 

caaagatttt caaagttttt attaagagac ttttaaaaaa tatttattca tttatttaga  44640 

tggagtctca ctttgttgcc caagccagag tgcagtggca tgatcttggc tcactgcaac  44700 

cttcgcctcc caggttcaag tgattctctg gcctcagcct cctgagtagc tgggactaca  44760 

gatgtgcacc accacacacg gctaattttt gtctttttag tagagatggg gtttcaccat  44820 

gttggccagg ctggtctcaa actcctgacc tcaagcggtc tgcctgcctc cgcctcctaa  44880 

agtgctggga ttacaggcgt gagccacctt gcctagccct gttaagagac atttaaaaag  44940 

ataaaaataa atggagagaa agccatgttt gtggatagga agacaatgtc acaaacatgt  45000 

tggaccctcc caatttcatc tgtgtactta atttaattcc agtcagagtg ccagcagatt  45060 

attttgtgga acttgataag ctgattcaaa atttatataa taaagtaaaa attctcagta  45120 

gccagtatac aactactaga aatgaggact taccacaaag atagaaaatt cggtaaacat  45180 

gagctggtac aaggacagat aaattgacca acaaacagat gaaagtgcaa aacagaccag  45240 

cacatgcttg gaactttggt gccagacaaa acaggcagcc aggtcaggag gggaaagagg  45300 

agctgcctca taaatagagc tgaggtttgc caggtagaaa aggttaatgg atccctttta  45360 

taacacatgc caacatcagt tccagatgga ccaaggatgt caatgtcaaa taaattctta  45420 

gtagaaaatc cgggtgcata cgtttttccg gattttttcc ttcctgtctt ctgctcttct  45480 

gtttctcttt tcctgcctta ctgtggattt atttatcatt taggggaaac tctgtcttta  45540 

tttattgata gtatttttga gtatatccct ccctgtagtt tttttagtcc tcgctcttgg  45600 

tatatacata acttgtcatt atttatggct acttgtatta ttttatcact tggagcgtag  45660 

catagaaatc ttacttcaat ttaagtttct tcaccctccc catttttaaa gtacaattgt  45720 

tggaagtatc ttatccgttt atggtgagta ccacatgtga tgatgtctgc tagttgctcc  45780 

aactataaaa agtgacttaa gaaactcatg agaagaatgg actgttatat ttacccttac  45840 

tttgactcat ttgaacattc ttctttcctt ttggaagttc caaatcttat gattttcatt  45900 

ctgtttagaa aatttccttt ggccattccc tactgggaca tttgcaaaca acaaaatctc  45960 

ttcattttcc ttcatctctg gatttcttta tttttccttc attcctgaat ggtatttctg  46020 

caggatatag aattcacagt tgacagttct tttctttcag taccggaagc atgtgccact  46080 

tctttctggc ctctttggtt tgggtttctt ttgaagattc gaagataggt ggattctcag  46140 

aaaagctgtc attttatatg acactaagat agggaaaaca gtgccaggta aaacaggatg  46200 

cactgtgggt gaaaaggtat gcacagattt cagaaatgtg gctccgtgag aaaaagcaac  46260 

tggggactgg gcacatgagg cctcgaggag cggtacctcc agccctagac tggctgcatg  46320 

gtcggcccag ggtgtgcaga gctgcaggtg ggctggagac ggggtgccta ccatgcaatg  46380 

aatcctcagc aggggacccc tccctgctgg cctcctatgt aggaagccct ggtgatgtga  46440 

cagtgaatga gacacagcct cacctctgac acggttccag cagtgtgcta ctggccatgt  46500 

gccagataga gcagggtccg tggccaccga gggcctccgt aagagggaat cagggagcgg  46560 

aggcaggctg ctcttgaggg ctttagaggg cttcatgccc cgggtagggc ttctgtgatt  46620 

ctgcggggtc tccagtcctt ccagcttgag cactgcactc gactcatggt aaatattatc  46680 

agcaacttag aatatttagg cactcccctc agttttatgt tcgtcatata caggctttca  46740 

caaaccattt tcttttttct ttttctaatc ataacattcc attcctaggg tatgtttgtt  46800 

aattttcatt tcactgggtt gtttttttga ttgtgtgtgt gtgtgtgttt gtttgtttgt  46860 

ttgtttgata cggagtctca ctctgtcacc caggctggag tgcagtggcg cgatcttggc  46920 

tcactgcaac ctccgcctcc cgggttcaag cgattctcct gcttcatcct cctgagtagc  46980 

tgggattaca ggcatgaact accacgcccg gctaattttt gtatttttag tagagacggg  47040 

gtttcaccat gttggtcagg ctggtcttga attcctgacc tcgtgatccg cctgcgtcag  47100 

tctcccaaag tgctgggatt acaggcgtga gccactgcac ctggcctttg cttttttttt  47160 

tttttttttt ttttgcccgt tctacttcac tctcatgtgc tttcccattg gtttgtggtt  47220 

ttgctgttgc atcagcttcc ttctataggt caaggctatg taatgtaccc agaccctggt  47280 

cctggggctg agggaccagt tctgagggat gcttgatgct tttacagttc tttagccttt  47340 

aatctttttg tagaatgcca atgagactcc tccttccagg acagctggga gggtcgggaa  47400 

gtcctcagtg aatgttcatc atcaggaaaa ccttggtgga tgatgggcag gagggaagct  47460 

tcagcagtgg gtccccctcc ctgaactgct ggttagagag aggcttgagt gctgtagaca  47520 

aggaggtctt ttatattgtg ttgtgcattc taagtggatg gtctttgggg gaagaaaaca  47580 

atgtagagta aaatcaggac aatttggtct atttgagcga aggtctttct gaactcccaa  47640 

gtgtttgttc cctccttccc ctcagagcac aatggttatt tcttaaattt atttcctatg  47700 

agacaggagt aattatgggc agagggacag atgagagctt caagcattgt ccagttctgt  47760 

cccgggacag ccctcttgga gagagaacca cctgtggcag agactgtgga ttgctgtaaa  47820 

ttatcttatt aattggaaca tcacttgtta tattggagca attatagcat gttcaaagct  47880 

ttgctggaag gccctccaaa tgccgacaca ccctgctggc atttcagtag tgctggtggc  47940 

ctctgtattc gtgagttttg gactcagtgg aatggagctg ggctccatag caccttcggg  48000 

gtccagaagc cagtggcatg gtgcatgacc gtggagacgc tgcccatgaa gaacatagag  48060 

ccagcctgaa ggagaatggt accaccgaaa accagtgggt tgagaatgag acccttgcat  48120 

cagcaaagtg agtagcctac ccattaggca tggtatgaat cggaaacctt agtgaaacaa  48180 

aaacacaaag agaggagaat cgggaccaag aaggaaggcg ggtgaagccg catcatctcc  48240 

ctcctcgggc tggctcaggg ccccatgaga tgcaggtttt ctggcacaat tggctcctcc  48300 

tggagtcctg cctcaggctg gtcagaattc ccatgctcca agagtcagaa gggacacatt  48360 

agaaagtctg tgtggtctcc tcaaaagcca catgcctcat gtcagttttc atttcttcct  48420 

cgtcgcgatg gatctttcga gtgcttgcca ggggccaggc cctgctgtaa acacctttca  48480 

tgccctaact tggcagattc cctgagaact ctgaagtagg gcctatgtca ctctcctgcc  48540 

atttatagag gggctgcatc tccccaaacc acacacaatt cgtgttaggc tgaattgtga  48600 

ctccctccac cccctgcaca ttcctatgtt gaatgatgcc ttaacccgaa ccccaggatg  48660 

tgagtgtttg gagaaagggc ctttacagtg gtgactggtg aaagtgggtc ccttagggtg  48720 

agccctcatc caacatgact tgtgtccctg tagaaggggg cgatcaggac acagacacac  48780 

agagggaaga ccatgtgagg acacagggag aagatggcca tctgtgcacc gcagagagaa  48840 

gcctcgggag aaaccagccc tgccaatgcc ttgatcttgg acttccagct gctagactgg  48900 

gaggggatac atttctgttg gttcagtcac tgtgtggtat tttttatagc agcccaagct  48960 

gactaatact cccaactcgt ggaataccag gattcctctt aactcacaga gctgtggaca  49020 

gagtgaaaag gaaaaggaat gaggttcgtg ctaatgagct agaggtggga aacccaagaa  49080 

tcatgtttga gtcctgctcc agctgggtgg tgcgtgtgtt tccctccagg tgcaggtgag  49140 

gggaagtgct gaagcctcgg cctcctcaca ggtatagatg gacgagagtg cacaccttta  49200 

agagttgttc tgagggtcaa gtaagcccac tgagcaccgc gcagatagtc actattagta  49260 

aaatagtgat aatttataaa gataacttat gttttctgaa caaagataaa atgcattctg  49320 

agtctctgtt tatatttact gcaatgagag tacatctttt tgttaactga gtgaagggtt  49380 

taagtgaagc tgaggtttcg aattcttacc taacacagga ttcccagtgt tgcattcctc  49440 

attgctcaca ggacgcttta gaaatactgg gtgaagatgg caacgcctgg ttagggacct  49500 

ggttagagtc tgaccagtga tattctctca aaagcagcag tcttccagtt tctgaaacta  49560 

catgagaaac ccccattagc tgcctgtggt ccctggcaca tgggctggtg ggcataaggg  49620 

atgcagatgc cccgagtgcc acaggggttc ttagacaggc aggtccttta agggtgtctt  49680 

tgattctatt caggtccatt gaaatctgcc acatagaata aggttttcaa gtcatggtaa  49740 

gagacttctg agattacagg ggaggtttct ccccctgggc cttatgtgat ttagacttcc  49800 

atggtgcagt cattgataca gtttggatat ttgtcccctc catgggggca gatacttcat  49860 

gaagggcttg gtgctgtcct catggtaacg agtgagttct cactgttagt tcacacgaga  49920 

actgattgtc aaaaagagcc tggcacctcc cctcctctct ctctctctct ctgtctctct  49980 

ctctatcact ctctcactct ctctctctcg ccttcctctc accatgtgat gccagcttcc  50040 

tttcacaagt ccagtgggag tggaggtaga caggaatgca ctggcatggg gtggttaggc  50100 

cagggtgagg gtgtgcagag tgcacatcaa tggaagcttc ctgaggccct caccaggtgc  50160 

agatgctttt tctacagcct tcagaaccgt gagccaaata aacctctttt taaaataaat  50220 

tgcccagcct cggttgttcc tatatagcgg tgcacatgga ctcagacagt ggttgtagga  50280 

caaaatgatg atcctggacc aggactcctc gggacttcag ctgttgagcc accaggctaa  50340 

agtgaccttt ccttagaagg gctgtggcaa agttcagcac atgtcatctg tgtcccatgt  50400 

gccgtttcta aaggaaagcc agattctctg ggaattctgc ctgaaaacag aaaacatcaa  50460 

gacttcctgt cctgtggaca agtccagtta tgagactgga attattctgc ggactaaaga  50520 

cttggaacca agcatcttag gtacagcctc ttcattggca tagaccctcg ccggtatcat  50580 

cttgagctgc ctgaagcttt ctctgaccgc tgtccactcc tgtgtggacg tggtgtatac  50640 

attatggtaa cctccattct ccatcatgat aatcagccca gggctctcaa agcctcttat  50700 

gcaggttctc tctctgcttg tgaagggcaa tacttcctct gtttgtgggt ttttgttttt  50760 

gttttgtttt ggctcagcat aaggaaagct tccctgagga gggtcagatg gctcttttct  50820 

tttctggtgc tgctttgcat accctcaccc tggcctgact gccctgtgct ggtgcattcc  50880 

tgtctgtttg cactcccact ggactggaag cagctttgag gcaaggacat tgtgtcactg  50940 

agtctgtttc ctgttgcaag taaccagtcc caactcaaac tggctaaagg aacaagagag  51000 

gagaaaatgt aactgttcgc aaagtcaaag ggtgaaagct atcgagtgtc cagggacagc  51060 

tgaatggata aacaaaatgt gatctatgca tgcagtggaa tattactcag ccttaaaaag  51120 

gaaggacgtt ctgacacgca ctacaacatg gaagaacttc agggacattg tgttcagtga  51180 

agtaagtcag tcacaagaag acaaattctg tatgattcca cttacatgag gtccctagag  51240 

tcattgaatt catacataca gaaagtggga tggtggggac ttgggtggag gataggaaat  51300 

tatttcaatg gggaaagagt tatagttttg taagattata aagttctgga gatagttggt  51360 

gtacgaaaaa gtgaatgtac ttgatgctac agcactgtac acttaaaaat ggctaagatg  51420 

gtaaattttg ttatgtatgt cttatcacaa tttgagaaaa ataacgaaac tcactgagca  51480 

gctgtgggtg gctgtggcct cagatttggc ttcatgagga ctccttggcc actcagcggg  51540 

tgggtctctc tctctgtctc tctcacacat ttatttccag tgactcccta gaccctgatc  51600 

ttctcagctg tgtgttggct ctgtctgcag gcttgatgtg gtctctaggc agcctcagta  51660 

gctccacttc agtgtcatct ttctttaaag tctagaagga aggaagtcat ttgttttctt  51720 

gagaactcaa accaaagcac atttttttac aactctcatc ccttgtaggt tgctaaggga  51780 

ctatgtgagt ccctggagga actggcctca cttagtgcat cccaagtgta aaaactgctt  51840 

gggaaacact cactatgaag aaaaacgctg ttttcactgt ttcaacatta gaattctcta  51900 

cacaacacca actaaactgg taaatgtgtt ttctttccag tctgatcaaa accttgaata  51960 

taaatgggac atcttcaaag aataagagaa aatagggctc caactgtaat gaactattgc  52020 

atctacattt tctacttcct tttgtgttat tgcttaaaag gaagactgtg gcatggtctc  52080 

ttttgaaggg gataattcca attgtgatga gaatgtcata aaagggtcac ccggcttttg  52140 

gtggacagga ttcccatttc agccctggct ggagcaattc tggcttcact gggggaataa  52200 

gaaccttgct tcctttaaaa agacagaaac aatttatcct tttgagagca tttctcatat  52260 

ttgctgaaat cagttgacct taagctgtag aacaaatttc atattatttg tattatgttg  52320 

acatcaggat tttaaaaaga aaagattcaa caccaagaaa gtatttattt atccatttgt  52380 

gggtttttca tcatttttgt ttgtttgttt gtatctgtag gactttgatt ctcatcggaa  52440 

accatgaaaa tgcttttcca gtgttggggt ggtcactaat taattctcat tatatctggc  52500 

tgcctgccat tttctctttg ctttcaagaa ggttggttaa atggcctgat tgttcataga  52560 

caaataacaa aagaattata ggataatgac tttttttttt tttttttttt gagatggagt  52620 

ctcgctctgt tgcccaggct ggagtgcagt ggcacgatct tggctcactg caacctccac  52680 

ctcccgggtt caagtgattt ctggctaact tttgtatttt gaatagagac ggtgtttcac  52740 

aatgttggcc aggctggtct caaactcctg atctcaagtg atctgcctgc cttggcctcc  52800 

caaagtgaag ataaggactt taaaaaaaaa aaacaaaaac aaacaaacaa aaaaataaaa  52860 

ctaatcacta ctgaggaaac tccaatacaa agtcttgctt ttctaaatta gaatttaaaa  52920 

attcctagct aaataaaccc tagaaatcat ctaatctgat cccaattgaa gtgagtctgt  52980 

aaatgaagat cctgaaggcc ccaggggttg acaatgtgcc caacacccca tggtttatgg  53040 

cagaagagct caggctagaa cttggagatc tgagctgttt ctctgcagca gccccaattc  53100 

cccgcctaga aatgtaatgg aagaaggata cgagagattt gatgttccat ttttttagaa  53160 

ctctctcaaa taatggaaaa agatacttcc tatttaactg cataataatc ccgggatgtg  53220 

actaggaggg aggaaagaat ggagagagag agagagagag agagagagag agagagagag  53280 

agagagagag agaaatagtt agttaggtgg atagtctcac ttacttctga aagtttattg  53340 

tgaatatgac tgtgtattta tgggccaaag attgagactg tatttttagg tagttaacaa  53400 

aactcaagtt tcttcacttg gataggagac tataatattg acctcagcta aatttatttt  53460 

atttttcatt aaaggtgata taaaacattc aaaggcgatt tgtagttact aattgatgta  53520 

tgagtgaata atttttatgc cttatcagga acacgggaaa ttgggaacac aggaaaatgc  53580 

tgattttgtt tttaatgtca catgtcctga ttttttgcta agtaagttat ggttcctgag  53640 

gatgaacttt gatgtttgga tccctcatga atgtttaata tgtctgacaa ctccttacac  53700 

atttaggttg caggttttgg ccaggctcta aggcttccga agagcgagcc agtggccctg  53760 

cctgagcccc gtgggtttct cctcttcctg ttaacttata tgtcatgtaa atagtggccg  53820 

ttggagaatg agtggtatcc agcttcccac agaagcctgg atgagagcat aaaaatagat  53880 

cgtttggaaa agggcccgtg accctctgtc acccttgttc tgggtaaagg aaatgaagga  53940 

ggtggaagcc gagaggagag gagcatagac attcctgaag tcccagaacg acgggcacgc  54000 

gcctcccaag ttctagcccg gtcccggggg gctgccccgc agcagcagcc ttcccggcca  54060 

cctcaccccc gcagggcacc agggacacca gctgcttagg cggaatacca gaaagtgaga  54120 

tgagtgttgt ttccacacac taacggtatt atgcctcctg ctctgggtct gagcagcaaa  54180 

gggaaaatgt gagaatattg tgggaattaa gggcagaagg aggccgagcc agcaggatgc  54240 

tggaactaaa aggagcgtct gttcagggcc caagatcggc tgtggctggc agggctgtgc  54300 

tggcgtgcac acggtctaaa cagcatccct gtgtggcctc tggagcctcc cacgttgtgg  54360 

aaacacatct tcatagggga ggggtgcatg gcctcaggaa gacggctttt gccttagtag  54420 

aagttggcct gcaccggaaa accctccatg tagttgcttt gagggaccat tatgctcact  54480 

gtggtgccct tatgtctcca cctctgaagc agagagacag gctgccacag gcgcagggct  54540 

ctggagagag cagcgggctt aatgcctccg cagatgcccc tgtccaagac ggtgcaaatc  54600 

ccatctgctc ctcaccccgg tcatccccac cccgggccat ctcctgggct cttctaggta  54660 

cagagctgag gatacaggca cctgatcgcc ccacaacaag gagctcagcc cacgtcctgt  54720 

cctcattttt aacattgcta aaaatgttca tggtagttta accgtgaaca tcaaatgtac  54780 

aagttgagca acaacaacaa ttctgcctgt tcttatggtg agccacattt ctagaaatga  54840 

agtgaactca tgcaaaaggg tttgcagtag gtagatcatc ctcacttgac tggtgcattt  54900 

gactatacga tttttggtgc acctccccca gccctgccgg ctcctgttct gtgcttgcta  54960 

gatgctcagc agggacagtg cagaggagca cttagaaagg gacccaggct cccgctgcct  55020 

cgctctcctc ttccgttaag catgggcaca tctcgaggag ctgtgcagac ctaagggaag  55080 

tggagatggt aggtgccaag cacagcgcct gcagggtgta ggttctgtgt aaagtgtagc  55140 

tgctgtcagc atcctccttg ctgtctgcag tcccagtcac tggaagtgac tgcactgacc  55200 

tgaagatgtg acactcaccc aacttatctg ggaatgccaa ggcccatcta ataagtggat  55260 

taattgctgt ggcattgagc tgtgtggcac tctgttagcc gacttgcatc tctgagcaca  55320 

ggcaaagacc aaggaccttc aggagaaatg gcccaggaag cccaagtctc cctgtgctga  55380 

agtccttggg ataaacatgg aatctgatgc tttgagcagc cccttctcca aataaagggt  55440 

taagtcctgt cacccggtca ggaactggtc tgacagaggg aactacacag ccagagtgcc  55500 

ccagagttgg tgctaattga atgataaaca aagccacttt catgggaatt gctgggcttg  55560 

ctgttttctg ggacaagcac tgtgataaca ggaacaaagt ggattttatt ttccttcagc  55620 

ctcttctcat ttggtgaaat tcccaggcgc catgggagtg cattgagggc ttctgagtca  55680 

tggcatgggg tcttctagag ccttgaggca cggggactct gtaaacaggg atgtgaagca  55740 

ccagggattg cccccgtggc tttgtgggaa ccactaagag caatgtcagt catagaaaca  55800 

ggtactgcat gctgtgctgg gtatgtgctc ctctcttata tgactctttg aaagctcaac  55860 

caaccaacca taaggtgggc atattaaact tgattaataa actttttttt attccaaagt  55920 

tctgtgctgc ttcttggcat gagaccctag gaactgatca accaactgtc cacctactcc  55980 

tctgaaccag acccctgagc agtatttcca cgtcatgctc tgaacctctc cctctaacct  56040 

ctaagccttt gctagttcat tcattaattc acaatgtgaa tgacatggag ctcctacagg  56100 

tgccagccca gtgctgggga cacagcagtg aatggcagga gtggcccctg cccaataagc  56160 

aaagaaccca tgaggtggtt ttgtcagaat gcatgccacc catccttcca ggatggcatt  56220 

catcaaatgc cacttgctcc aggaagcctt cagatgaagc tccctccaga tgaagcaagt  56280 

ctccctgtgg gtcctcctgc agctcaagag ctgcacctca catgttcctc catgcagtag  56340 

taatttgcac atggtctcat ctggctgaca caagcaggac acgcaggcac tccctgtttc  56400 

gcttttgttt ctctcttccg ttctccggct ggtgtaggcc atgttagtgg aaaactggtg  56460 

cccagcaaag acattttatt ttttattttt attttttaat tttattatta ttatacttta  56520 

agttttaggg tacatgtgca caacgtgcag gttacacatg tgtacatgtg ccatgttggt  56580 

gtgctgcacc cattaacttg tcatttagca ttaggtatat ctcttaatgc tatccctccc  56640 

ccctccccct gacattttat ttttttattt ttatttttat tttttgagac agagttttgc  56700 

tctctcgccc aggctggagt gcagtggcat gatctcagct cattgcaacc tctgcctccc  56760 

aggttcaagt gattctcttg ccttagcctc ccgagtagct gggattacag gcacacacca  56820 

ccacacccag ctaatttttg tatttttaga agagacgggg tttcaccatg ttggctagga  56880 

tggtcttgaa cttctaacct caggtgatcc gcctgcctcg cctcccaaag tgctgggatt  56940 

acaggcatga cccgccgcac ccagccccag caaagacatt tttaatggaa aagaaatacg  57000 

gacaaacaca aatggagata agtcatctta gtactgggaa tagaagtgag ggtgcagagg  57060 

gatggtttta aactccatgc atctttgttt ttctatccca gctttaatag aaagaaataa  57120 

taaattcagc aaacacttat tttaggacat ttcctgtggg ccatactggg aggaggggcg  57180 

gtcagtcaca caactgcatc tgctctatgg atttacaggt cagtcatagc agaaaacgtg  57240 

cacatgtatt catgacacaa actgagcatt tgccaggcct ggccttgaga tggtcatggt  57300 

atttacagtt gggtgcagca gacacaccat tcccaagggt cttaacagta tgttcataca  57360 

aacagaacat tagtactggg cttttctata atggaaacat gattaaatgt tgaaaacatt  57420 

agtgcggaaa ttggtgtctc gtcctttccc ccaaaatgga caaggcactg tgtttcagac  57480 

tttgtatttg atttttcaga agttttacta ttaagtgctt atgtgtaatt ttctttttat  57540 

taatccttct taggtttttt gtttgtttgt tttgtttttt aacttgtggc ttgatttctt  57600 

gagtctttta ggaaattctc agtatgtata ttttccaata ttgcctctgc ctcattcaat  57660 

ttctccacaa cttcttggac tccaattata ggtatgttag aatttttaag aatcatttct  57720 

catgtcttac tgtcttttgt gtatttctca gtcttgttcc tctttatgct tcagactgca  57780 

tattttcttc ctatttttct cccagttcac tcacaatttc ttttgctgtg tttagtctgc  57840 

tgataaaatc atgaactgaa tgcttaattt catttatttt gttttgagtt ctagagtttc  57900 

catttgatta ttctctcttt ctctctctct ctctatatat atatgtatac acacacacac  57960 

acacacacac acacacacac acacacactc tttaagttct agggtacatg tgcacaatgt  58020 

gcaggtttgt tacatatgta tacatgtgcc atgttggtgt gctgcaccca ttaactcgtc  58080 

atttacatta ggtatttctc ttaatgctat ccctccccct gcccccagaa tggcaatcat  58140 

taaaaagtca ggaaacaaca ggtgctggag aggatgtgga gaaataggaa cacttataca  58200 

ctgttggtgg gactgtaaac tagttcaacc attgtggaag acagtgtgga gattcctcaa  58260 

ggatctagaa ctagaaatac tattgaccca gtgatcccat tactgggtat atacccaaag  58320 

gactataaat catgctgcta taaagacaca tgcacacgta tgcttattgc gaactattca  58380 

caacagcaaa gacttggaac caacccaaat ttccatcaat aatagactgg attaagaaaa  58440 

tgtggcacat atacaccatg gaatactatg cagccataaa aaagaatgag ttcatgtcct  58500 

ttgtagggac atggatgaag ctggaaacca tcattttgag caaactatca caaggacaga  58560 

aaaccaaaca ctgcatgttc tcactcatag gtgggaattg aacaatcaga acacctggac  58620 

acagggcagg gaacatcatt tgattattct taatggactt cagttctttg gtgaaattct  58680 

ttttgcttct gctttcttaa acattctgtt cagttatgtt agtatctgtg gcttttaaca  58740 

tcaatttttg aactagctgt gggcgttttt tctgtgtgtg gggtggtggc agtcttggtt  58800 

ttcatttgtc atgtttcctg gcattgatga tcattttttt acaattaaat atttgatact  58860 

gtatttttag agtatagaca aagtcaggct ctgggtgggg gaggcatgtt ctttagagag  58920 

gatataattt ttcttccagg ctgcctaatc agatcctgtc atggtcctct tgtttctagt  58980 

ttgtagccct tcaagggtct caccttgaaa ccttgtggtg tttgcaaagg cccctcttcc  59040 

taggtgcatc ttgaactgcc gtttttggtt acttagcatc cactaagaga ctgccacaat  59100 

ccctgctgat cttttttaga ttcgtagcag ctggctttgt cttgtttact gggcattggg  59160 

ccctgtacct ctgccactta ggactcagaa atgccttgag gggaaacatg ctcagagtgt  59220 

tgactctgtc tctgcagtcc tcatttctct gagaccttgg cacttccaga actggtgcct  59280 

tggtagctct gaactccaaa cttggtctcc ccagaacagt gtgattacca ctgctagttt  59340 

gtgtatggcc cctataccac atgcttccaa acgggtccat gtctgagaag gaaaaatggc  59400 

catggatctc ctgctccctt ccctggaggt tttggcccag taagccctgg ctgccttggg  59460 

cgatctgaat gggttcaaac tattgttgtt agtattttgt gtagctttca taattgtcct  59520 

tagtggaagt ttaactcctg cactgtaact gaaaattaac atgctctctc tttctagtac  59580 

tggctttgag ctgatgcagc tgatgtggcc atctttgata gataagggtt tacagattgt  59640 

aatgtctcca agattgttga taagcatgtt tttccacctt tcttgacgac ctgcagtgaa  59700 

caatctaaca ttctggcttc ttctacctca ctggataaac atctgtttaa cctctttctc  59760 

tttagccata acattgaaca tttgtgtaaa ttattcatcc tcccttttag cctactaatg  59820 

aaccctctgt ggtgggtagc agtattaatc ctatttatcg gtgaggtggt aaactgagaa  59880 

aggtaaaaca aattacttta aattcaaaca caaacctccg gcttgttgag ctatttttat  59940 

tattccacag ttatgtttta aacatactct catagcatat tttttttttg ctctttttca  60000 

ttttaaatac tcttaagtct tggggatatt aatttataga gttttcaata atttataatt  60060 

attgaataat tgataagtta actttaattt cagtgaattg ttcgtcttta aatatgaaag  60120 

attagagatg tatgcttcag gtcaggatgg agtaacagag acttgattta ttatcctgac  60180 

tgaacaaaca aaaaatggac aaactatatg aaataatggc ttccaagcca atgggcatca  60240 

ggcagtgaaa gacaacgatc cctgaaaagt aagaaacaaa catggtgaca gtacagttgt  60300 

cccagtttac cgcctagaca aagtttccag gtgtaaggca gggagaggaa actcacgcag  60360 

aatctgggag actctgagtt gggcatttgg agttgaaact ccaggggacc acaatgactt  60420 

gcaggatgga gagaaggctg aacagagaga gagctgttgg agatctgcag aggatccgcc  60480 

atacgtattc aactgagcgt tgggtaggag gacattaggg acattgaagg ccagggaaag  60540 

aaccaaatga aaagattgga aagagaggct aacccagtgc taactcaaag ctgggaagag  60600 

tgcctgttct catgagcaag agaggaaagt atcaagattc actgggcatt gagtgatata  60660 

cagaagggtt ttgcccagta gtgggggata acttgcacta gatggagcat gactccaggc  60720 

cttcctaaca aatgtgaaga gcaagaccca aaaagataaa aatgtttcta agcaacttaa  60780 

ctgcatccca gaataaagtt caagaatatt tataagaata caaaaatatc cagcatccaa  60840 

aaacataaaa tcacagtgtc tggcattcaa tcaaaaatta ccaggcaatc aaagaagcct  60900 

gaaaatagca atatagttaa gagagaaagc aaaacaaaac taatgaggac acaaaactaa  60960 

tgttaagatt atgaacatta agacaaggac attaagacat ttatttttac tatgtttaat  61020 

gtgttcaaaa agttaagtag agtcgtggaa catataaaaa gacccaaacc aaacttcact  61080 

ggagagagaa actccagtgt ctgaaatgaa aaataaccta gatggattta acatttggct  61140 

gattttggat aaaattacaa aagcaattca atgaagaata gatagtctca acaaatggta  61200 

gtggtaccat tgaatatcca tatttaaaaa actaaacttt gttgatatat atgcctcaca  61260 

ccatgtgtaa aaattaactg aaaatggatc ataggcttat gtttatagtt tcttccaaaa  61320 

ctattacact tttggaagaa aacagaaaaa catgttttgt gactggatta ggcagatact  61380 

attttagata caacaccaaa cacactattc ctaaaagaac aaattgataa actggactta  61440 

aattacaaga ttttgttctt caaaagattc ttaagtgaat atatgcacag gcaacagact  61500 

cagaagaaat atttgcaaat catatatatg ataagggact tgcatctaaa atatataaag  61560 

aactcttaca actgagtgtt aagaaagcaa acaacctagt gaaaaaaagg aaaaggattt  61620 

gaacaaacat tttaccagag aacacataaa aatgcctatt aataagcata caaaaagatg  61680 

ttcaacatca ttagtaatta ataaagttgc aaattaaaaa cacagtgtta taccactacg  61740 

ccagcactag aatggctaaa attcgaaatg ccaaccatac caagtagggg caggattgat  61800 

ggtggggatg tgaaatgctg caagtattct gggaagcagc tttgcatttt cttaaaaagt  61860 

tacatagaca cttaccatat ggtccagcca ttccatccct aggtattcac ccaaaagtgt  61920 

ctaaaaatac tcattgcagc tttatatgta gcagccccat agtggcaaca acccaagtgt  61980 

ccatcaacag gtaaatggac agagaaaatg tgatatgtcc atacaatgga aaagtactca  62040 

ccgttgaaaa gcaatgagct atgtatacat tctacaatgt ggcggaatct caaaataatt  62100 

tcttaagtga aagtagagga aaaaaagagt ttatatgaat gattttattc atgtagaatt  62160 

ttaggaaatg cacactaaag caaagtgaca taaaccagat gagcaggaga aggggctgga  62220 

ggaaactctt ggaatgatga tgtaactgtt aattatctca atcatgatga tggtttcatg  62280 

gacgtttaca tatgacaaac tgaccgaatt atttacttta agcatatcca gttttttgta  62340 

tattagttat acctcaatat ataaaggtgt ggtttttaaa gtttcatgaa aaattaaaca  62400 

tttaaagttc actttttctc taccaaggtc tattagataa cttaggatag ttgttaattt  62460 

aggcataact ccagacattt tgtgtgctga ttaatatatt ttaaaattct aggccacgcg  62520 

tggtggctca cacctgtaat cccagcactt tgggaggcca aggcgggcag atcacgagtt  62580 

caggagatcg tagccatgct tgctaacatg atgaaacccc gtctctacta aaaatacaaa  62640 

aagaaattag ccgggtgtgg tggcaggtgc ctgcagtccc agctactcgg gaggccgagg  62700 

caggagaatg gcgtgaacgc gggaggtgga gcttgcagtg agtcgagatc acgccactgc  62760 

actccagtct gggcgacaga gcgagactcc gtctccaaaa aaaaaaaaat tctctaaggt  62820 

ttccttagga aaagaattcg tgctaaataa aaatagtaat ttttaattca tattgaaatg  62880 

acgtgtgacc aaaaaagtgc ttcacttcac atatgtgggg ataccatata atttttagaa  62940 

tgttcattct gtcttggtag agatggagct tgtttacctc attggagtga agtgcattcc  63000 

atttgtgaat tgatagtgca aattctgtag agatcaattt tttttaaaaa accaggatat  63060 

tacatcctgt atgtggaggt aatttagttg agtggtcagg gctttccctt gctttttttg  63120 

gatataattc ctcactggtc tgaataatcc acagaccagt gctcattggc acctggatta  63180 

atgaaaaccc cctaggtatt tcatcttcag aaatcacata tgctgttgat aattcctttc  63240 

agagtattct tagtaaatgt catttttata aagtgtgatt ctggtattca gttttattat  63300 

tggttttcat ttgaagggta aagaaggtag cctttttttc agtataatta aaataacaca  63360 

tatttcaagc atgtgaggtg atagtcctgt gagttgtagg gaaaacagca ttatttggaa  63420 

atctctaaat ttcaataccc tctccaggaa atgaataata tggagttttt ttctacatta  63480 

atattctctt atcaatcctc attagttttg aaacagaaaa caaactgacc agtatttcta  63540 

ataatattat tttactgacc atggtagatt tgtccatttc ttgaagcctg gtttaaaaaa  63600 

agaaaaaata taaaaggtaa gatgttttaa atatccagaa ataatgcagc tgctgggcaa  63660 

gaaaccaaac agaaattctg tcagaggaat gtgcctgggc tcaggcatgg gacacaagca  63720 

ggtttgcgtt ctggcccacc tgcgagggtg gcttctgcac cccacggtgt ggcctttgaa  63780 

gcagcggggt ttgacctgga aagcagcagc atgggtttgc accctcatag tgctcgatgt  63840 

tgatggccca gttaccagct ggggggaggg tagggaccaa aggaaggtgg aggacaccta  63900 

ggccgcccgg ctgccgcagg gcctgcactt atggtcttta ttgggagaag tcgcctgctg  63960 

gtttgcagag gaaaggccat gccaattcta aagtgaggtg cagcctagat catggagtgg  64020 

agagtacatt acaggacatc agcctttgtg ggggatgggg ctgggaggac cagcccaggc  64080 

ggcccaatgt gcatctcctc acatgaccag ctcgtggtaa tgggctggac actgtggggg  64140 

actgaattag gtcgctttat ttttggaaac agtgatgggt gagaataaac ccatgcttgt  64200 

gggtgcaggg ctggccgcct cctccagcct attacgggta gtgatgtcat gttcagtatg  64260 

gccatggatg acagaaagcc tcaaagtcag cactgtttct tgtggaacat gcaaaagcag  64320 

cagagattat gacttctcca gtcctacaac cgaggtctct ctgcttcctg tgttcccgct  64380 

acagaaccac gaagctgccc tgagacgctc actcacgctg tggggatgtc agagagcccc  64440 

atcggaccca aatccacgat gctccgggct gatgcgtcct cgacgccctc ctttcagcag  64500 

gcttttgctt cttcctgcac catttccagc aacggccctg ggcagaggag agagaggtaa  64560 

gaagatggat ctttaaactt ggcacaagtt ccccttaaag acccagaatg ctgagaggca  64620 

tgtgggacca gcgggggctt gctcttcaga gaagctgaag ctagaccagg cagggactgg  64680 

cctgaagatg gggcggggca ggggaccagg gctgtgtgca cgacactgct accgccgggg  64740 

acaggtgtat gtggtgacat acgagaaaat atagggacat acaggaaata caggaaaaat  64800 

cagtcttaga gggcttctgg tttacagaaa gacctggggg tgggagaggg tgggtattaa  64860 

cagggaaaaa tggcctattt ctgcttcaca aagatactac ccctgaggac attcatacgt  64920 

gagaccattc cacttgctca gagtaggaat aagtttcttt atgctttgtt gtatgaacac  64980 

gtagctccct atttaacttt ttaaattcta cctctgttct ccttaaaata aaagaggagc  65040 

cctcatttaa ggacattacg catagactct gtacccatga atgttccatt gctagtgaaa  65100 

tacgtgtgtc acgtggtgtg gttttagctg tctttccgta ctcgtaagtg gttggtaatt  65160 

tccagtagtc tttgtggtat ccgttaatca actggttcat ctagcaagca tggattgagg  65220 

actgatggtg tatctggcag ataaaggaga tggggcagag ggatcatgct gcgaggagga  65280 

ggggacccac agtgaaccaa cggcctggct gcgggggatg aatgtgggtg gcatccctgc  65340 

ctagtgctgt gggacaagac gggagggcat ttctactccc gagggcacac gtgtatgtgg  65400 

ccacaggtgc tggctaaggg ctaggaaaag gcttcccagt gggtgcacag ctgagctgcg  65460 

tcttaaagga cgaaagggcc ttgacccggt gaagatgcag gagggaaggc gcaggggccg  65520 

agggagcagc atctgcgcat gtggaggcct tcatggggcg gctcccctgg gtgccctcat  65580 

gcgggctgca gcatccaggc atgaaatggg ggcttgaaag gcaggcagcg tgagctcaga  65640 

gagggcctta gtgtacatat tttggaaaat acctcctgtg ctgcctggag ggcctcagca  65700 

cccacttccc catccctgtc ttcccgtgtg ggtgacgctt gctggtcttc aggtgtctct  65760 

ttgtacctta catgctgtct tggtcggctt gtcttttgaa cagctcctct tctgcagaac  65820 

gccagtgggt ggagagcagc cccaagccca tggtttccct gctggggagc ggccggccca  65880 

ccggaagtcc cctcagcgct gagttctccg gtaccaggaa ggactcccca gtgctgtcct  65940 

gcttcccgcc gtcagagctc caggctcctt tccacagcca tgagctgtcc ctagcagagc  66000 

caccggactc cctggcgcct cccagcagcc aggccttcct gggcttcggc accgccccag  66060 

tgggaagtgg ccttccgccc gaggaggacc tgggggcctt gctggccaat tctcatggag  66120 

cgtcaccgac ccccagcatc ccgctgacag cgacaggggc tgccgacaat ggcttcctgt  66180 

cccacaactt tctcacggtg gcgcctggac acagcagcca ccacagtcca ggcctgcagg  66240 

gccagggtgt gaccctgccc gggcagccac ccctccctga gaagaagcgg gcctcggagg  66300 

gggatcgttc tttgggctca gtctctccct cctccagtgg cttctccagc ccgcacagcg  66360 

ggagcaccat cagtatcccc ttcccaaatg tccttcccga cttttccaag gcttcagaag  66420 

cggcctcacc tctgccaggt aggtgtgttt ccagctggtt ggaagggccc ctctgtccat  66480 

tcactgggga agggaagggt tcagacctgc agctgagctg gcatatctct agtgctgggc  66540 

tgggcacctg gagaggaaat ccagagccgt tggggtactt ttccattttc ctcgtccaaa  66600 

accaagcact ggctcaggct tttcattcac tcttcttggc ttctgtgttt ggccaccttg  66660 

gattccttcc agttgtagaa agtgcagaca tttgcagtgg ttctactttc catgtcactt  66720 

gggaacatgg ctttttgtaa ataacaaatt ccttgtcaaa ttaaattaat tcatccaaaa  66780 

cgtcattatg aaatatttca agtgtataag aagcagtgtg gtctatgggt tgaacaacac  66840 

caaccttacc ctctctttcc tcactacctt cctatgtatt cttaaaatgt attgcaaagg  66900 

ctcaatccaa gcatcctgtt gttctgtttt gtgttataaa acagtcactg cctcctccaa  66960 

ctcagtcatt tcaaaggcag ggttcccttt ccttagaaca tcgctcgctt gcttgccctt  67020 

ggcatgggat ttggacttct gggatcacag cagatgagag gttgcaagaa gaaaagtgcc  67080 

catcatggtc actgttttta aattttgctt tacagatagt ccaggtgata aacttgtgat  67140 

cgtgaaattt gttcaagaca cttccaagtt ctggtacaag gcggatattt caagagaaca  67200 

aggtatgtgg ggaggatgag ggcctccttg ggcatctgcc ctagtgcccg cttcgctgcc  67260 

ttgtgtgaag atgggccctg cggtgggaac atcgggcagc cgtggccttc atatggattg  67320 

agtttgagca gggcccacac gttattccat gcctcctggg gacatgctac aacctttaag  67380 

tttttatagg ggaaaactca ctactaatga gggagttggt gaggaatggg ccccagccat  67440 

gagcattcca gtgtgtaggg tgtaatttct ggctgcttgc accagccact ggcttgccag  67500 

tgatgccagc ccacaactgc tgactgtgag gaggagacac actctcctgc atctccatga  67560 

aaccagagag gacagggtga ggaagcagga gagacaccct cctctgagaa gtcagggaca  67620 

ctgtgtgttt gtgaacacct acataagcac ttaataatga gacccggttg tggacttagc  67680 

cgcatgcctc acacacaaac cagacagagc atctctctgc ttggtacaat gtcaggcttt  67740 

tttttttttt ttttctaatt tgaaatcatt aatactaatt tttgagcaat gaatatttga  67800 

atattttgag catcactttt taccagagca tgaatagaag agatgtggga gaggaaggct  67860 

agcaagctct tctgggcagc cctgcttgga gacagcccct gggcaatgag gagaattcat  67920 

aaggtgcttc cctcggctgt gggatggctt ttctccctgg atgctgtgtc tcagctgagc  67980 

gtaccttcct ctggatacct cattttggca gtgcatagag tttgttgctt ctgggatata  68040 

cctcagaaga gatggtgtgt gactggcaag gcagggcagg gccatgcctc cagtgcctgg  68100 

aagacggagt caggattcct aggaaccaaa gtgaatcccg gtggccacct ggtggaggct  68160 

ggagtgaaag agggaatggg ttggtttaaa gcggtgagaa atgacaagct gcccgcagtc  68220 

agcaggagac ccacttggct cctctgtgcc tctttacctc aacttcagaa gaaaatcaag  68280 

ctctctcctt atgaagatgc ctcaggaatg cctagaaatg aatagttgag tggcagaaaa  68340 

atagctctgt ccagctctcc actgaaattc tgctattcag ttatgtagat gacagaaatg  68400 

gtaagaatgt gcatctctta tgatctcaaa gaagcgattg tcattttaag tggaagagag  68460 

agaaaaaaaa gcctgtggcc tggaaagacc ttcatttccc tgaattggcc tttgtgaaac  68520 

actgctcacc atggctgagg gcctctctgc ggccggatgc tgtgtgcctg ttgccaccac  68580 

cctggccctg cttgtgtctc aagaatcccg atgactgtgg cccccagtgc ctcggcacct  68640 

cctccagctg gccaaactga gaggtgccta tccagcacct aagagattct gcacagaccc  68700 

ttccactcta ttggtgccgt cttctagggc agggcgatgt gtggggctgg atgccccctt  68760 

ctctcattgt gcaatgtcat tgtagcaggg gggatctgaa acagacagat ttgggttgga  68820 

gtgcactgct ggcttcctcg gcagggtagc aaggttcgag cctgccgcgg gggtttgctg  68880 

agagcagtgc catgtggaag gtacctgccc ttgctggcgc ctggtagatg caggataagt  68940 

ggatgtggat gtgcagtatg tgtaggggct gctgttggca tgtgcttgat cttcagcaca  69000 

cattgtagaa ggtttgctgg gaggacccca tctcaggatg gccaacatgt gcatcgagtg  69060 

ttggtttttc cagctgagct ctaaaaggat aactttcatt ttctacatat tttacataga  69120 

agagacctgt gcagacgaac cttctactgc ccgtgtcaga gtctccaaac agcggaaggc  69180 

tgcccttggg tgtcatttat ttggatttta actgtcagat gtgccttttt ctagaaaagc  69240 

tacaatgaca tttcagggtg atgcaggagg aaaaaaaaca cccagataac ctctttggga  69300 

gtgcaatttg tcacatactt aattccttga ggtttcttaa agctaacata aaaatacctc  69360 

aggaggaaaa gaggacctta aagtaaaatc aaaattaagt actactgtcc cagttgtact  69420 

tctggggtgt tgcttctcca gatgcttctc cagatgcagg gcgcgacagt gtgagaaggt  69480 

gcgaggagac tcacttgcct cccctcccct catccctgtc tccaggtgag gaatgcgatg  69540 

ccagtgccag ggtggagcac gcagctgctg tgtgcagtgt gtggacgctc gtttttccaa  69600 

cttcagcaca ccaggctcct cagcctactt ctgtttggaa aaacagcggg tctaaaattc  69660 

tcctcttact cccattgcct gtgcaggaga gcacagcccc cttgcacccc tgcagcctgg  69720 

cagctggggc ttccctcctg gcatggggag aactggtcgg agcaaagccc gtgttccctc  69780 

cactgccatc cacaggtgcc caaagtctca gtcccgtgag gcttctacac tttatttacc  69840 

acagagaagt agaaccatga cttacaaaaa gaaaagctct gaggtatatc acagttgaaa  69900 

caaaatgtaa gtgatctttt gtcctactta gagaaaacaa aaaagtaggc ccggcgcagt  69960 

gactcactcc tataatccca gcaacttagg gaagctgagg tgggaggatc acttgagccc  70020 

aggagtttaa ggccagcctg ggcaacatag tgagacccag tgtctaccaa aaatttttaa  70080 

aaattagctg ggtgtggtgg tgtacacttg tagtcccagc tactcaggaa gctgaggtgg  70140 

gaggatcact tgggcccagc aggttgaggc tgcagtgagc tatgattgtg tcactgtact  70200 

tcagtctggg caacagagtg agagagccta tctcaaaaaa ataaaaatta aaaactgaaa  70260 

aaatgtcatt cacgttcagc ccccaagttt atagactacg ctgtgagaaa acgtgcacca  70320 

gaattcaggg tttattccca gggcctgtgc cctgccccag gaggcccccc acccagccct  70380 

gggtcccttg catgggcggc tgcaggcctg gctggagcta ccagcagtct cgggcatgca  70440 

cggtgagcct gcctgtgttt tcctgcccat ccttcccact gcgtgctgtt tagaagctcc  70500 

tgcttcatcc ccaggggcat gttgagctcc tccccgtgcc ctcatcctgt gcacagggcc  70560 

acggtgcaga cattgaaaaa tgtgtaaaag aaaccattcg tttcatccta tggccagaca  70620 

gatgccttgg ctgtgggtcc ggtcaggcct gggggcatgt gaggggcctc tgtgggagtg  70680 

cgccgtggag gtatttactg aggcatgccg ggggcatccc agcacttact ggttcatgtt  70740 

ctgcgccctg atcgcttcca ggcagagcct ttggcattcc agaaaggcag catttccatg  70800 

gctgtaatta tgtataactt tatactctaa atccccagtt ttcccttttt taaaataaag  70860 

agtaaatgtc tagaaaagaa attctgagat gtagtctagt tatcagggaa cactctggct  70920 

tgtctgggca gtatcgagtt gaggttacta ttaccctaac ccactccctc ttcttggaaa  70980 

tgccagattt tggccatgaa ggagagagat tttttgaagc aatgattatg attagttgaa  71040 

tgcctaccag cctcaccagg gaagctgggt gacccactgt gcgaggccct gggttggcgg  71100 

gcacatgggg aatgtgtcct cagccccatc caggctgggc ccatttggcc acatcagcca  71160 

tggagccacg ggataggggg ccacctgcag gccaggtttt tgttacttcc ttggtgaatc  71220 

ttggaatttg tattaaattt tcagtaacat tttgggtatg ccctttctat catcagaaaa  71280 

tgtaattaga aacttctttc ctggccaggc gcagtggctc acgcctgtaa tcccagcact  71340 

ttgggaggct gaggcgggtg gatcacaagg tcaggagatc aagaccatcc tggctaacat  71400 

ggtgaaaccc catctctact aaaaatacaa aaaattagcc agacgtggtg gcaggtgcct  71460 

gtagtcccag ctactccgga ggctgaggca ggagaatcgc ttgaacccag aagtggaggt  71520 

tgcagtgagc cgagaccatg ccactgcact ctagcctggg caacagagcg agactccatc  71580 

tcaaaaaaaa aaaaaaaaaa aacttctttc cttttatgct gttgaaagag ttcatgttct  71640 

catgttctaa aatctttaag aaaaatgcca cagggggcag tgtccaagca gaggcagggt  71700 

gttctgcgac agcctccctc ccactgcctg tttctcccct ttgtgtatat ttggatctgg  71760 

tcttgtttct tactcagcgt gagccttggt ttcctgggct gtcaggtggg gaccatcatt  71820 

tggacatcac aggtattgtg ggattaacag aaatcctgtg ttcttccatg ggcagcccac  71880 

aggacagtgc ccggcacctc agtctagcta aagagaggga tgttcctgtc ctttctgcct  71940 

cctcaacagg caggcccacc catgaaacat acacgacacc acagagacct ccctgaaggt  72000 

ccctcaactg catggacatg tagttcttcc agccaagcag agggatcccg gccaggtccc  72060 

cactgatcca gtttgcaaaa agagtaaggg gagaggacct acccaaggtt atgagtgggc  72120 

atagaccttt gtccacccgg cagaccttct tgtctttctc ctccctttct ccagccatcg  72180 

ccatgttgaa ggacaaggag ccgggctcat tcattgttcg agacagccat tccttccgag  72240 

gggcctatgg cctggccatg aaggtggcca cgcccccacc ttcagtcctg cagctgaaca  72300 

agaaaggtaa ggttactgct ccctattgat ctgttcagct catccacaga gaaactctgt  72360 

tggtttattt ttaggctaat aaaataaaag atgactttaa caatactcac aaattttatt  72420 

cttagtattt attttttcag gtatatttta caaagttttc accttattta agaaagaaca  72480 

ttaatttgtt aattttattt tctattgttt tgaataggta atccatttca ttgttcaaaa  72540 

attagaacca tgggataagg catccactaa gcccgttttg cttccatttc ggctctaccc  72600 

ccctcaccac cctgtcacct cccttgggca accatctgga gtagattcgt gtgtgtcttt  72660 

tcactggtta cctgtccaaa tgcaggcaaa cacatttttt atatgaaaac tagcatactg  72720 

ttgagtacta ttcttgtatc tatacccagt agggcatttt tagatggatt aaaagtgata  72780 

ctagaataag cctagactca tgagatgatc tctaatgcag gtaaaggact atgcctgcct  72840 

gaatcctttt tgcattaaaa atcatggcaa aaaccataat gacttttgca ccaacctgta  72900 

atagaaggat ttctattcct ttgggtataa tacccagtaa tgggattgct gggtcctatg  72960 

gtattactgc ctctaggtct ttgaggaatc gccacgctgt cttccacaat ggctgaacta  73020 

ttttacactc tcaccaacag tgcaaaagca ttcctttttc tctacaacct caccagcatc  73080 

caccaatcat atttctaaga ttgcttgtag ctgttgttct ctttggaagt tctggctttc  73140 

tatcttatga aaatcctaca gccaattgat ccattctatt gttggtggac acttgatttt  73200 

cagttttctt ttttttttct ccccctgccc tttttgcccc attatactca tctttgtgtg  73260 

ctaccatgct gcagactaga ctaaggaaag ggaagctatt ctttcactct gtctgtctcc  73320 

ccaaatggaa attgtggact gaggggacat tgcaggtcgt tggttcccag taaggacagc  73380 

ttgattcact aggagtgggg aaatcagaag cagctcggat tttaaactcc ctgtgtttat  73440 

agaaaagtga gacacccacc tggttcactc atgctctgtg cctaatacct gagagaattt  73500 

ttccaaattc ttggatgaaa cctctgcttc atgcttcctg gagaaaatcg ccttggagtt  73560 

acaccctgtg gaatgtatga tttggctgcc aggaggtcca gcctcaggca gggctgtagc  73620 

gtttccggga aacatagatg ggttcatttt ggcacaggta atggtgtgag agtggaaggg  73680 

gtggggagtg aggctgggaa agacccgggg ctcagtcaaa gctcagcccc gaagcctgtg  73740 

gctactgatt gtcctgaagt gaagtagaga gaaggcgttg tgtaggggag aaaggacaga  73800 

taattcttga aaagtaggat cttctagcat ccagaattcc agcataagaa gcccaacacg  73860 

atgctatttc tgagtggaga taagggcttt tgtagctgga gagctgaatt agacctgatt  73920 

gttgaggact gaaactgaat aatgatgatg gcaggaaaga gggtcgcagg accaagagca  73980 

tctggcgagt ctgcagagat gagagattat tgggagagga ggaatgatgg atggttttgg  74040 

ttggctcctt cgtttccgtg taaagtttta aagcaaggac aaataacatt tctgcatgca  74100 

ttatcttttt ggaatctaga tgagagtata taactgtttt tacctctgtg cgtgcatcct  74160 

gcctctctga cagactttgg actcaatctt aagatgaaag gaacaaaata ggggatatta  74220 

gaatagcaga cttgaggaaa ccgagtgttg ttggtggcct ctgggtgaaa tcttatctga  74280 

ctgctgtgtc ttcatcttgt ccctggattt gacattcaga tttcacaatc caaggataga  74340 

tttgagcaaa gagtttacca ggtcataaag agccacaacc attcaccata ccacctccag  74400 

taaactggag atgggacagc tagggacgtt ctggatgctg ttctccagag agccctggcc  74460 

agaaggactt cccactgagc catttctcac aagtggaatc cagacccacg cttggtgtcc  74520 

ccttcagttt ggaagccagg cgtcattttc ttcccacaac tgaatgtcaa tatgttctta  74580 

tcccacttta attcaacaca gccttttatg gaatctgatc atttcctttt ctgcaagctt  74640 

tactgccctt gtgaaatgct gacacagtga tatttgtcat gtttataaac atcttttgga  74700 

agcctactgt gggcaaggca ctggggacca agcccaactc cagtggatct tgctgccagg  74760 

aggtttccaa caccagaaat attagaagtt taggcagaca tgccccaatg gagggtgatg  74820 

aaggaagcac tggatcccag aaatacagca cactgtgaag gtctgttgga ctcattagca  74880 

tagggcagtg acttcttgtt cttttggttg tgctgtttgt acttttccac tctcagatag  74940 

ttttgccatt cagtggcttt ttatgatgtg ttttctcttt ggactcatgg gctggcctaa  75000 

agcagatgca ctgtttactg ttaatagcaa tgtggtagag tgctgctccc gtgcagctga  75060 

gtgcttgctt tctggaaggt tttaaagatc caggctcctg gttaaatccc acccagaaga  75120 

ctgacctcct tccagctctt ttcagtgatt cattataggt atcattttgt gtctgagcct  75180 

ttctcacctc tcctctttgg gagaggattc agctggagat tcatgatcct ctttcttagc  75240 

tgcaagctca ttcccttcgt tggggattct tgcacaatgt ttgagggcct ctcccaaggg  75300 

acctctccag cccccacact gtcattgcaa gggttcccgc cctgtatctg gcctagcctg  75360 

tgctcatcca gctgtcctgc agcccggcta ccattcctag gacgaagatg gttcttggca  75420 

gcctcttttg cagtgactgg actcgtattc agagaagagc cttttcaact gtagctcctg  75480 

gcttttatgt tctctctatt gaattctccc atgctcccat tttcaaaaaa ttcttctttc  75540 

tttaaatttc ttgccacagc tggagatttg gccaatgaac tcgtccggca ctttttgatc  75600 

gagtgtaccc cgaagggagt gcggttgaaa gggtgctcga atgaaccata tttcggtgag  75660 

ttgcttgaga ggttgctgtc aatgttctga actcatgagg cctggattcc ctctgctcac  75720 

caacctgaga tttgggacta tcactcttat ggtggtttac tcatatttca gtccccagtt  75780 

ctgaaatcct gctgatctgc attattatct ttaagataaa ctagatttga agttgttctt  75840 

aaaagctctg tcaaaaccaa acaaatgaaa agcaccatat cagacgtagg aattacagac  75900 

gtcaataaga ttctatccta gttggcaggc aggtaagtcc tgagaaggtt ggagctccag  75960 

catgacccta tcccacagca caaggaacaa catagagctc ccaacagagc accctccctt  76020 

ccctgcaaat tgggagcctt ccctacctca cgagcttgtt ggaaagatga cttgagcaat  76080 

ccacacaaag cacagtgcag ccttaggcat cattgttatt agagctttgt taagaagcat  76140 

tgtgcagggg taatatatat ggttgaagtt ggagttggct tgatgtcaac cctcctgatt  76200 

caagatccaa caaactgtat gctttagtct ttatataatt tggtaatgat gtgtctatga  76260 

taagaatgat aaacagttcc atttacttac ctctcaacta tcttgtggaa ctttatactt  76320 

ctttgaagtt ttacacaaag ctgcacacta atctaacata ccagttgcta aaaagataag  76380 

ggctcagcct ttgcatccgt ttcattccag ctgataaatt ggctgagcac acaacatcta  76440 

cagcagttgt tgactcttgt ttgctgtctg tccactttgc agggagcctg acggccttgg  76500 

tgtgccagca ttccatcacg cccttggcct tgccgtgcaa gctgcttatc ccagagagag  76560 

gtaaggggtc ctcagtgcta gtcaggctct gtgtagattg tctgcagtca aggccaccgg  76620 

ttttagagat ccatgaagat ccactgagaa aaataataag actggaagtt ttttcgtatt  76680 

ctcttggttg aacccaagaa aaggccaatg agttcatcca aattaaggag agaagaggag  76740 

attctacttc actgacagct cccagatagc tttacatcat ggattttgat gaaagatttc  76800 

tatagagcaa agattctgta gtttaaaaat ataaaaccct cagacaaaga aggcttcagg  76860 

gtcattgaca tttaattttt acgtttctac ggaatgggca aaatgttgat gttgttgaac  76920 

ttagatgatg gatgcactgt tctttttact tttatgtttg ttaaacaata tccataatga  76980 

aattaaataa cacccacagc atgtcagggc gatgtgaccg tatgtcccac tttcctaagc  77040 

agtcacaact tcacataaaa atggtctaac ttaatatata ggtaaatgtg atttactttt  77100 

caaagtgtca ttgttcatat gactaattcg gtgattagaa aaatattttg ttaggccttg  77160 

tcatctctac ttttattcag aatgtgatca tggtttctat gggccaaatt attgtcccaa  77220 

agagaaactc ttgactctgc aaaaccattg catgtcacca tctgggaatt ctgtcatcaa  77280 

attgtctaac tttgtcatga ggattcttgg tcaggagcag gactcatttc tgtattttct  77340 

tgccccttcc tacagatcca ttggaggaaa tagcagaaag ttctccccag acggcagcca  77400 

attcagcagc tgagctgttg aagcaggggg caggtcagta aatgcagctc catttctaca  77460 

tctggtgact ggggagaaaa aggactcact gacacaactt ccttttgcac ttcagtattc  77520 

aggtttcctt tcttttctgt gagccttgaa ggaggtttcc ttttatagaa gcttgcacag  77580 

agctgggtgg ggtgcagttg ttgggacatc agcaaggcct tcatgggccg gtctaactca  77640 

agcaagacta aattcagtgg aataaatgtc aagccctgga tttagtttgg gggaaaatat  77700 

agtaagacag gatgtgggtg atctgtctcg gcaactgtaa atgtaaaaat gttccagaga  77760 

catgactcaa caagtcactt gacatgagtc aatgatttga cccacactgc cagcaacccc  77820 

agtgagacat acaacaccca agaaccagct cgccagacag agcaggtcac ttaaaaaaat  77880 

tattcataga gtttcttttt tagagcagtg acagattcac agcaaaatgg agaagaaggt  77940 

acagagatac accatataca cgcatagcct ccccgctgtc aacatccccc agcaaagtga  78000 

tgcacatgtt atggttgatg aacctgcatt aacacagcct cgtcacctga gtccctagtt  78060 

tagggacttg atatttaggt tcaccttgat gtcatgcatt ctacaggttt ggacaaatgc  78120 

ataatgacag gtaatcaccg ttacagtatc atagtgaata gttttattgc cctaaaaatc  78180 

ctctgtgcct tttctgttcg ttctccctcc cccaccaacc ccaagcaacc actcatattt  78240 

ttattgtctc catattttca acttttccag tattgtcata tagttgaaac catacagttc  78300 

atagcctttt gaggttggct cctttcactt agtcatatgc atttaagttt cctccatgtg  78360 

tttttatggc ttgatagctc attttttttt agcagcaaat atttccttgt ctgggtgtat  78420 

cagtttagta acccattcac ctactaaagg acattgtggg tgctttcagg ttttggcagt  78480 

aatgaataat gctgctctaa acacccatgt gcaggttttt gagtggatat aagttttcaa  78540 

ctcctgtgcg tagataccaa ggagcgcatt cctggattgt atggtaagag tgtgtttggt  78600 

tttataaggt acaggcaaac tgtcttccaa tgtggctgtc ccattttgca ttcccactag  78660 

caatgaatgt gagttcttgt tgccccacat cctctccaga atttggtgtt gccagtgttc  78720 

tggaatgtgg cctttctaat agtagcgtag tggtatctca ttgtttctga tgacttatga  78780 

tgtgtagcac cttttcatat gcttatttac catctgtata tcttctttgg tgaggtgtcc  78840 

ataaaggcct ttggcttgtt tgtttaattg ggttttgttt tcttattgtt aaattttggg  78900 

aattcttggt gtattttaga cactagtcct ttacctgata ggccttttga aaatattttc  78960 

ttccatttca tggcttgcct tttcattctt ctacagagca gaagttttta attttaataa  79020 

aatccagctt attgatttcc tgttttatgg attgtgactt tggtattgta tcttaaaagt  79080 

caccaccaaa cccaaggcca gctagatttt atagtttcaa attttacctt taagtctgtg  79140 

atccgtttta agttaatttt tgtgaaggaa gtaaggtctg tgtcttgatt cattttttat  79200 

ttttttgcct gcagatgtac agttgcttct gtaccaccag ttgaaaaatc tgtcttttca  79260 

cagttgtatt ccctttgctc ttttgtctaa gatcagttaa ctatattcat gtgggtctac  79320 

tttcgagttc tttaattgac ctatttgttc tttcaccaat atcacatttt cttgattgct  79380 

ttagctttat agtaatcctg gaagtcaaat aatgtcagtc ctccaacttt gctcttctct  79440 

ttcaatattg tgtttgctat ttttgatctt ttgcctttct gtattaactg tagaatcact  79500 

ttgttaatat ccacaaaata agttgctggg atttttattg agattgcatt gaatctatag  79560 

atgaaattag gaagaactga caccttggca aaagttgagt cctgctgtcc atgaatatgg  79620 

aatatctctc catttattta gttttttgta tctttcatca aagtttaata gtgttcctca  79680 

tatagatctt gtctatagtt tgttagattt atatgtaagt agtttttggg aggtgctact  79740 

gtaaatggta ttgtgtattt aatttcaaat tttacttgtt tattgctggt ctgtaggaaa  79800 

gcagttgacc atttgtacat taaccttgta tccagcatct ttctgtaatc gcttactagt  79860 

tccaggccag gttacttttg cagcattaga tgcagtcgta gtggccccag tttaagaagg  79920 

ttgtaaacaa accacacacc atagggctct tgtggttctg tggccatgag ggagggacac  79980 

agctagagag gacagtgggg actgctgact ttcaaaccct gactttcaaa actgttttaa  80040 

gtttttcatg caaggtaggt gtttattgtc agaaatgttg gggagggaat ttctgagtct  80100 

ggtagaaaat tggactagaa atacctccat tctgtacctc atatctgcag agtagtttac  80160 

aggtgtaact ccacaatgaa ggtgtatgaa atgtataggc attttcttat ttcctctaca  80220 

atttgtatta ttcttctatg tagcttttcc ctgtaaaatt atacatcact gtgtctgtta  80280 

ccaagctaaa gtaaaattac tctgttttga atggaatttt gtagtgttta agttatttta  80340 

gactctcctt ataggataag ttatctgtgg ccaaaacaaa ggtgaaaata gcttgcccca  80400 

aattgcaagt gtgctaaaac tcgaagctcc aaaatgaaaa atgtagctgt ggtcatgggt  80460 

ttccggccat gttctgctac tcaggatttt gatctctggc aaatcactta gccatgcgga  80520 

cctgaggttt gtatctggtc agtggggata ataatatttc cacacatagc agttgaaaag  80580 

attaaatgaa taggacattg acaatgcctt gggagcattt ttctggccca agaggaatgg  80640 

cctttcctgg gaagccggcc tcaccctttc ccttgtgagg gacctgggct ggtcctgggc  80700 

cacagcccct aaatctgttt tagggggtcc ctggagccca tcatggttct tagctttctt  80760 

ctgttaaagt aacagtggac cctgtctgtg ggtcccagtg aagtgcccag aaggatgcag  80820 

gaatttactg tagacctatc tgatgagcag ctcactcact ctcaactgag gagacagggc  80880 

tacaaaacca gctccactct gatggattta tttgtttcag ttgcaccttt taaaaatgta  80940 

tttgaaattt tgaaaacctt taattagtgg ttttaaaatc acaacttatg catcggcagt  81000 

gttcaagaaa gcgcagaaga acggtgatag caacaggcac agagcacttg tcctgcccag  81060 

cttattgtct cctccccttc acccacaggg cgtgtgggtg tagtgtcctg tcatcccatg  81120 

tcatagacag aggacccaag ttggcagctc tggctcctga atggtagatc taggcctggc  81180 

attcagctcc cacgtccagc tgtgcccata ttgtctcagg gacacagccc tgcccattca  81240 

gccctatatg gtagcaccag ggcacacgca atttcacttt tctccttaag cttcttagtt  81300 

atcctgcatt cacccagtaa gtgtggaatt aataaatgaa ttgaatgaat ttagttgatc  81360 

ataacagtgc atcctaatag cacttgtttt tagatattaa aactttctct tctatcttga  81420 

cttatcattt ttaagtgcac ttccatcttt taaaattacg tatgaaatgt atcaataact  81480 

ccaaatgttt tttaagggtg ggtcttctta gagtcaagac ttcattcaga acttggagtt  81540 

tgtatctgat catctgagtt gggcatttat atatgaagct taaattatga ctgccttgag  81600 

cttctttcct ttaaaaatct catttctgaa acacattgag agctgcgaat gtctgctgtc  81660 

cattacatta accgcgattc caagccacgg aaccaggaca gcagatctgt caccagagga  81720 

gtgaggctgt cacagtgacc acccctcagc tagtgtcgtc ttcacctgga ggattggctg  81780 

caggtgttta gaatcagtgc agaacaacca ttgtagcaag acggtggaat tattgcaatc  81840 

tctgatgacc tccagcaatt tagtgagttt tctttcctaa actgaacttc atctgttgtc  81900 

ctaattcact tagagtccta gactcctgga tgtgcaatgt tctttgagat gatcatgtcc  81960 

aatttccccg ttataaagat tcaggaagct gaaactcaga aatattagca gacaactcac  82020 

aaagatggga ataaacttgt aatgctctcc agtttaatcc ctttttttaa atattaaggc  82080 

cattatgcct ttgttccaat ctctaaaaca atttctattt gtgttttaag cctcggttct  82140 

taattgtttc ttgttgaagc agaggaatat aatataatcc tgaaaagaaa gacttacttc  82200 

ttttcagtag ccttctaata gatttcccag aaatgttgca gttgcatttt ttagcatatg  82260 

gtaggtatac tttttttttt ttatagagtc ttatatgttc tttaagtttt aaaaatggaa  82320 

aataaaagaa aaggaaaaat gaactactca tagatcggtt gcccctatgc agcccctgaa  82380 

tattgggagg aagagtggac agcaggtaaa gtgttctcca gcccaaagac cactcctgat  82440 

gtcaagcaga tccaatccta tgctgccttt ttccttgtac ttggggtcat gctgcctgta  82500 

cgattctttt ctcttctctt agcataataa gtttacccat ggtttttaca aacataatgc  82560 

aggtctcatt tttttcatgg ctacacaata gtccatcata taattcacct ccttatggat  82620 

gttcatttac catgtttcta atttttaata ccacagacaa tgcttagagg accatctttc  82680 

tgcattattt attttttctg aaatctggat tgttgcctta ggacaaattc ccacatgtgg  82740 

gcctcagact tttgttctgt gttatcaagt ccctttccca gagtagccta gcaattgaca  82800 

gaactccatg ccatgggtct ggtgggtgcc ttcctggtaa ctcttactgg gcactgaatc  82860 

ttcacctctg gccaagagca cctgtcaagt ggcattggat ggtcttgggt caggtgcagt  82920 

tggacaatca taggcaggcg caggcatgcc tgttctctgc tggagagagg ctttggggca  82980 

cttggtgtca gttggttgat gtgtgctccg tagaacagcc tccctagtgg cagcattttc  83040 

ttctctgctt taaggaatga tgacatagtt cctgcatttg gggagagaga ttccccaaac  83100 

agcagattgc taccaaactc tagccagcaa gactgctcct catcagaaag ccatctgtga  83160 

ctccttcaag agagcatggg tctgggttgt ggcagctgtg gttctgtgtg aactgattga  83220 

gattgtgcca attttgtgga attttcctag tagttaggtc aaaattttcc cttttttctc  83280 

tctttcataa ctgcatgatc agcatgacag taatgctaat aaaatcaaag gcggactgtc  83340 

cctctcgtga agtctgtttt gaattctcca ggctccctcg cagctcctat ctgatgcaca  83400 

catgcttttc attttcccgt tctaatcata gcagacgtgg tttttattct gctttccctg  83460 

ctgattgctg atgacgtctt tccatgctgc catgtgattt tcctggttac cgcttgctgg  83520 

ttgcttggta ttacaccgag ggagctaatt tcacccctct ctcatttcta atgtgtttct  83580 

ggtttttccc actgtaatga atatgtggca caaatgtctt tccctgaagg ttagctatcc  83640 

tatgtggtta cagaatattt cctttctcaa tctcctcaga agcgggacca ctaggttact  83700 

tctaggcatt tcatatccac ctgataaata tcgccaagta tactagtcgg ctctcatgat  83760 

gctaatacag ccatatctga gactgggtaa tttataaaga agaagaggtt taatggactc  83820 

acagtttcac atggctgggg aggcctcatg atcatggtag aaggcaaagg aagagcaaag  83880 

gcacatctta catggtggca ggcaagagag tatgtgcagg ggaactaccc tttataaaat  83940 

catcagatct cgtgagactt actcactatt acgagaacag catgggaaaa acccaccccc  84000 

atgattcaat tacctcccac caggttgctc ccaccacaca tgggaattat gggagctaca  84060 

attcaagatg agatttgggt ggggacagag ccaaaccata tcaccaagtg atcatcaaaa  84120 

atagtgggct caattcctca gagtgtcttc agctataaac aatatggcct ttgcggtgga  84180 

tagaaaggat ggtccagcaa ctcacaagtc accctgcact gtgacaccca gggacatcct  84240 

agcccatctg tgggcttgtg tgtcaatgca ccctgtggca cacctgtcag accacctgcc  84300 

agcacacctt ccagtgcacc tgccaacaca tctgccagaa cgtctaccaa catacctgcc  84360 

aaaccacctg ccaacacatc tgtctgtgca cctgccaaca cacctgccaa taggcatggc  84420 

ccttgctggt tctgaaaagt cagacttaaa ggcaaagaga aaatggagct gcttcccagg  84480 

gctgcctacc ccaggaggac acggccgagg gagacaacac tacccagcgc gtaccgtgca  84540 

tccgagtgct gagatgtgtt gctgtagact gtgggaaaac actctttttc tgttaagtga  84600 

aactttagag gcctttaacc acggaattaa gacacccaca tgctcacata gagggacatg  84660 

tatacagtag acaaggggca agtgagtgag ggcagttctg ttcctcagga ggaagcctac  84720 

tcagcctttg ggcaggagag gccctggttt acttcagtga atgagcttca ggctaaggct  84780 

ggatgtcttg gaacacctca atttcaccca tgccccaaag tcacacgtgc acttatgctt  84840 

gaactgcagg gtcacaggct agaagggaaa gaagggttgt tatggagccc agttgttttt  84900 

cttctcccaa gaggagatgg tcagggacaa gacccacagc tctcccttgg cagcatgggg  84960 

agccaggaca caggtgaggc cgggccactt ttggcttttt ccagcctgtt ctctgagctc  85020 

actgcaagcc attccttctc ttggcaacca ggatttgagg acacatgctt ccctcatggt  85080 

tgtttctcaa gggcctctgg gctccttacc tataacagta gttgggtttc atattaatgt  85140 

gactgttgtc catacccacc ctgagaccag agaaggtgcc ttgggctcca cctgggacac  85200 

gagggtttaa tactgctgca gggcgaatag aaagctccct ctggctggtg ggaaggcaaa  85260 

gccacaccag gcgggtctgc tttgctctag taactcgctt attctctgcc ttgacatggg  85320 

agtaagtgca tccttggagc actcactgtt catgttttca gaattagggg caaaggccat  85380 

ctgccttaca tgcacccagc ataggccaca tgcgcaagtt gttcataaac ccagtctgca  85440 

catcagcaac tgcctgtgtg ttaacaggac acacctgtcc caatagttgc aactaacatg  85500 

tgtctccctt ggtgtcttcc agcctgcaat gtgtggtact tgaactctgt ggagatggag  85560 

tccctcaccg gccaccaggc gatccagaag gccctgagca tcaccctggt ccaggagcct  85620 

ccacctgtgt ccacagttgt gcacttcaag gtgtcagccc agggcatcac cctgacagac  85680 

aatcagagga agtgagtgcc tagagggagg caggagccgt ccagcagggg cggggctgtc  85740 

acgttcctct tgttcttccc tagtgtgagt agtcatccag gtaaatcatt agccgtcttt  85800 

gaggtcatga gtcacccagg gtctgtctag gtatttttct gtcattaaat acgtcctggg  85860 

aaccacatag gaactcttag catttgtttg caaggctatt tttcttagaa atcagtaaaa  85920 

taaaataaaa aaagacgttt ggcgttttaa aattacacac atacacacat aattgcaaat  85980 

gcaaaaaatc ttttaactca gttccttaaa aacactctga tactatgatc agagtccaat  86040 

gatcttggaa cctattgttt taacagaggg tcatttcctt tcaggtgagc gtatgacctt  86100 

gatatgtact atttccgttg gccaatttca aatgacttac gcctgagctg ttactgagcc  86160 

agttatgctg gagcagatgt tctccatgtg gatctttact gaatgcccag cataagcatg  86220 

gaacagagca gccacagggc tgttcctgtc tccctccctc cagaatgcca tccctgagtg  86280 

cagcctgtgg cctaggaaca gagcatttca gatgcaatta ttttgtattg tgtggttgag  86340 

gaggcacgtt ggcatcaacc gtggcagcag catgatggca gcagccatca cagcagacag  86400 

gccggcaggg gacactcaga ccagcctggc tgctttccca ggatgctccc cgagcagggc  86460 

ccccatgcct ctctgtggtg cccatgtccc tagaagcaag acattttctt catctgccca  86520 

aaccacctgg gaggttgaag gcaggatctt cccctctgta gcttcaggaa taagtgagtt  86580 

taggcaggtt tagctcatca cccttcatct gctgaaaaaa atgagcacaa agcagaacgt  86640 

gggttttgct ggtcagaccc gttcagtgcc cctgacactg accagtagat gaccctgggc  86700 

agggtcccaa tgcttgatgc tctcgtattt caatcctgca ccaaaatacc tatttcaagg  86760 

tttagtgtct caaatgaaaa gggcactcag caagtgccct gtgtggcaca cgcagggaca  86820 

gggtcagggt tgtggctcaa ccccaccatg ttctcagggt caggggcatg gctcagcccc  86880 

actgtgttct cagggtcagg gtcacaggca aggctcagtt tcacggtgga ctcagggtca  86940 

gggacatagc tcagctgtat ggtggactca tggtcaggtt cagggggcat agctttgctg  87000 

tttggtggac tcagggtcag agtcagggtt gtgccttggc tttatggtag actcagggtc  87060 

ggggcatggc tcatctgcat ggtagactca gggtcagggg catggctcag ctgcatggct  87120 

cacccagggt cccagttggg tatggctcag ctgcatggtg gactcagggt cagtgtcagg  87180 

catagctcag ttacatggtg gacacagggt caggggcatg gctcggctac atggctcact  87240 

cagggttccc gttgggtgtg gctcagctgc acggtggact cagagtcagt gtcaggggca  87300 

tagcggagct acatggtgga cttagggttt gggatatgga tcatctacct ggtgggctca  87360 

gggtcaggct cagggcatgg ccaggctgct tggtggactc aggcttacag tcaggagtat  87420 

ggctagactg cctagtggac tcagggtcag ggtcagggtc aggggcatgg ctaggctgca  87480 

tggtggactc agggtctgga ggcatagctt ggcgacatgg tagactcagg gtcagggttg  87540 

ggctccttaa ggaccctcac aatgttgact gttccctcct ccctgctgcc cttggaagat  87600 

atgttatttc ttcacaggat ctgttctatg tgcccttgtc agagttgtct tttttctgtg  87660 

tctctttagt ttccctgtat tctttatatt ccctggagat gggtcatgtc cacatcagtt  87720 

cagatctttc atactgtaag agatagcgtt tgagttcaga ctggctaatt ctagacaaaa  87780 

gggggatctt ctcaccaaca atcagcctta aaaggcacct gtttgagagg ggctgcaggt  87840 

ggctgcaggg tcaccttgaa ttgaagcaca cccaggctct gcctctgccc tagcctatct  87900 

cctggcctct ctcttcatct ccagatgagc tttactctgt gccggtgcag agtcattccc  87960 

agaaggagag gggtgacccc aaagccagct agactggccc agcctggaca cagcagagtg  88020 

ttgagttggg catcctctgg ggaccatgtg gactgggtgg atagcactct tggaaggaag  88080 

ggctgggcag gtgagccgga ggagaatgcc ccaggtggtc atgtcagtga ctaagggctg  88140 

tcaggtgagc ctggaaggag gtctctatgg gggtcgtatc agtgaccatg tggagtcctt  88200 

ccttaaggaa tattccttgc acagcacttt attgttcact cagtgctctc agacctgtga  88260 

ctgcatctga cttgggcatc tgtcctgtgg aaggggtggg ctggtaacat gatccacttt  88320 

tcacaggtga ggaaaccaag gctcggagcc tggaggctgt tagtggtttc cccacgatcc  88380 

tgcagccagc agtgtctggc agggccagag gtgcttcctt gtgtccatct cacaccctac  88440 

cagcttttcc agtttgttag ggcttttttt tttttgagat ggaatctcac tctgtcgccc  88500 

aagctggagt gcagtggagc gatctcagcc cactgcaacc tctgcctccc aggttcaagc  88560 

aattctcctg tttccacctc ccaagtagct ggaattacag gcacatgtca ccacacccga  88620 

ctaatttttg tgtttttagt agagacgggg tttcacatgt tggtcaggct ggtcttgaac  88680 

tcctgacctc aggtgatcaa cccgcctcag cctcccaaag tgctgggatt acaggcgtga  88740 

gccactgcac ccggcttgtt agggcttctt gacccgattc ccgccttcca cacggctgac  88800 

agtttcagcc tgtgtggtgc ttccgtctac tggtaacaac tgttctgccc agcttcatga  88860 

catctgttga ctttgaatga gcacgcactt tcttctctcc aagtgatgag taaaagtatg  88920 

aaatgttttc tgctggaaga atcttcatgt atgggagagc ccgcccagtg catcccccat  88980 

cacccaaaag ccctagtaac aggagccatc ctctctcccc catgtcccaa caggctcttc  89040 

ttccggaggc attaccccgt gaacagtgtg attttctgtg ccttggaccc acaagacagg  89100 

aagtaagaaa tttgcatttt tattgagcaa ggagtgtact taattctatc ctttagttta  89160 

aaaaaattaa cctctgtttt tctctttaat ttgcaaggtg gatcaaagat ggcccttcct  89220 

caaagtaagt tgctgagatt tctttacatt ctctccttgt ctgcagttgt actccaaagt  89280 

tgaattctct tccagatttg cacagggggt gccttataag aaaatgacta caccatgcca  89340 

atttctttta aaaaagaaaa aagtaaaagt gttctcatta tggacaagga tctggatgct  89400 

gttaactttt ctgccggctg ttggctggat gtgcaatatt tacatgtgtc atataacact  89460 

gtggcataga tacagggaga tggatggcac agcctttttg gccatttggg aatgcatggg  89520 

ctcagcagtg ctgaggtctg cacagctaga aggaattgct ccctttgtgc aggtgtgtgg  89580 

atgaagcggg tgttccaaat ttaccaaatg caacggagga gggccttcat cacaccgttg  89640 

ctccacagcc agtccaggca gctgttagag tttttttttt tttttgagac agagttttgc  89700 

tctttttgcc caggctggag tgcagtggcg cgatcttggc tcactgcaac ctctgcctcc  89760 

cgggttcaag caattctcct gcctcagcct cccaaatagc tgggattaca ggcgtccgcc  89820 

accaggccca gctaattttt tgtatttagt agagacgggg tttcaccatg ttggtcaggc  89880 

tggtctcgaa ctcctgacct caggtgatcc acctgcctca gcctcccaaa gtgccgggat  89940 

taaaggtgtg agccaccgtg cccggcttag agttcccctt ttataagcac acctttccct  90000 

ggctccctga gtaccgtggc cttgcttggc ctgggctcat tcctggccca gtgttcctgt  90060 

cagggccagc tgagggacct catcctaacc tcccacttgg aggcacaatg ggctgtatcc  90120 

ccccagcctg gtttcctcgg cataacccgg atttaatgac cacagtgcct gatcacaggc  90180 

atccttccct ggaatcctgt tttcaaatgg cttgtctgtc caggaagttg ctcagtgcat  90240 

gcgttagcag aagcggggag aaggagaaga gaccctggta ctgacgagct gggcttcccc  90300 

ggtggggact gtgttctggg cacactccca ctctggctgg tagcagaaac acgggctttc  90360 

atgtgcttgg aatttgtgac tgtattgggg ttacctgagt gtcattgact ggtcccttca  90420 

tgatgcggaa actgctaaat ttaaacaaaa aaaatccttc atttttctaa gaaagagaag  90480 

aaagtccttt gcccaggacc tggataggga tatggtcatt attgtgtgaa gtgcaggact  90540 

cataaaagcc tattaagata atggctctaa ttcttctaag aaaaataatt cgatgggctg  90600 

ttctttttaa acagctccct gaagtctatg tagtttgtaa tgcaggcttc caaggcctga  90660 

gaggagcgcc tagtgtattt ccccttcggt cccagtgggt gggagtgtcg aagtccagac  90720 

aggacttgca ttctggcatc atctcaggag cccctgagtc ccttgccact cgccttgcag  90780 

actgtggtcc agtatgtcag gactggggct caggaatctg cagggacagg tgcccaggag  90840 

attctggccc tggcgtgggg aagcatctat agaggaagtt gagcctcagc tttgattcag  90900 

gtcctaacct ggggctgtgg acagggcact cacctctcag cctcagggtc ctcactgcag  90960 

agctagagtc agacatccca tctgtaggtc tgtgaaggct ggaggtaaag tgcatgaaca  91020 

ggtggccagc agggtgctgg gcacgtggtt gatttttgat aggtgccact taaaattcct  91080 

cctgacagtg ccgctggcag ctggaggaag tagaagcttg gtactttgtg ggacactgac  91140 

cactctgact ggactttcct ttggcagagt ctttggattt gtggcccgga agcagggcag  91200 

tgccacggat aatgtgtgcc acctgtttgc agagcatgac cctgagcagc ctgccagtgc  91260 

cattgtcaac ttcgtatcaa aggtcatgat tggttcccca aagaaggtct gagaactccc  91320 

ctccctccct ggacccaccg atgcctctcg aagccctgga gacagccgtt gggtgagggt  91380 

ggggccccca ctttttacca aactagtaaa cctgacattc caggcccatg aggggaaaga  91440 

ggatcttcca gctctgcaaa aacaagaaca aacaacatca ccgtgaattg gcctttcctg  91500 

aaagtgactt atctgacaca tctctgtagc cacatgcttt ttgggtagaa gaagctgggc  91560 

atgggtgcac cccaccccct agggtcccca tgggaaaggg acatgcaagg aaacagcaca  91620 

gaacacgagg tggtccccat gtccctggca cactagcatt ccgggggatg aggaatcccc  91680 

agcccttgag gcagaggtgc cgagtgactg ccatgcttcg cccgtccgca tgggcgcttc  91740 

tgtccagctg cacccgaggc cgggggtttc cctcacctcg gtcttcccaa gatggagatg  91800 

ctaacgaaac tgagaagggg gcgtatgttt gacgaaggtt tgtgcaagtc aggcccttct  91860 

ggaacacagc agggcctaca acgaggggcc tttgcgatgg gctgtgagga tgggggtggt  91920 

gggaagaatt ggccacgttg gagaccccat gccaccccac catggtgagt gctctgtgcc  91980 

tcctgctcac ctgtggtgag ctgggcgagc tgggcgagct gggcgagctg ggctggggag  92040 

agcctgtgag gaccgagagg agaaatgaga agaaggaaca aaaatattat ttctatgtaa  92100 

tttatatttt acttatgcca aattatttat gataatttgc cattgctata ctgtaccagt  92160 

gtcaaatgct gcagcctgcc aagctgtgat tttgtgaggc ttgtccctat gtaggatgca  92220 

ccgcaggccc ctggccactg aaagagtgtg cagtggactg tgggtctccc atatgcggtg  92280 

ccgcccaaag gtggctttgc ctcaagcaac ctaccctgat gttttactca ttggaatgtt  92340 

tttccccgat tgtggatgac ttcttttctg atggagagag tccaggaggg atggaaaact  92400 

cctggattta agctcagcat cccccacatg ggcttttcga tcatcttcag gcctgaagct  92460 

gcacgacctg aagttcgcct gcatttatca gccctctttg tgctgctcct tgccaccttg  92520 

gggttcctgc tggggaccat gtgtggttgt ggcatgtgtg agcagaaggg aggatgagga  92580 

aaaagagaag aaaccccggt actgacaagc tgtttttgag tgccactgtt tgccatcatc  92640 

taagccactg aatcaagtgt atttcaggct tatttcaaca ttccaatgcc ctggttttcc  92700 

tgcttgaatc tgttcgtggt caaaggtttg ggggaatttg tgaccctgga acatccccag  92760 

agtgaaagat ggagctgggc cacatcagaa taaggccttg gccccatcct ctcacagcct  92820 

aggtgctctg caggcatgct gactgtcctg attgcgatcc agcccgaaat tccctcctct  92880 

gctttcaaaa gtcaaatccc ccattcttag gccacactgg tgtcacaagc tcctgtcagg  92940 

gagctggggt ttgggaatgt gctttgtgaa ctctgcttta aagtgagggg ccgaggaaaa  93000 

cttagaaaca ggcagagttg gaagcagcca aatcacagtg ggtgttgtgt gtgtgtgcgt  93060 

gtgtgcatgc gtgcgtgtat gcgtgtgtga aagcaggtgg accattccac tttttagctc  93120 

ctattgatgc accaaaccaa gtgcctcatt tctgtgccaa atgtttgcct tggtcgttgt  93180 

ggacctcctt ctctaacttg cggtggcatg actgtcagga ggtgctggca ttttcagcag  93240 

atcctcatgt gttgaccctg atgtctttag cagaggcctc tagcatctcg gtttttcatc  93300 

cactgcagga atgtggccac agggagcaga ggtttgtact ttccccaaga ggtcctcatc  93360 

ctgagacggt ctctacccat gtttaaccca aagagtgcag gccaggttcc ttatccttct  93420 

gatgaaggat gagagagctc atttagaagt cagagcaaac tagggtctca gtattgagaa  93480 

acgcagcctg ccagggaatc acagagacat cggggtgccc gcgatggccc tcatgaagcc  93540 

atgcctcgac ggcattcagg aagccctgca aacgtgcttt ttgaactcat tggccaggtg  93600 

tgatttttac acaaggtaaa cgtggtcaag ggcatcgggg aatttgctcc aagcagatag  93660 

ctccctctga ggaaccaaag gaagcaagtt tccacgattt ctgaagagct ggtataggaa  93720 

gtttctttct tccttttgtg ttacatgtgc attaaacaga acaagctgtg tgtcatcaca  93780 

gattgtactg tgggctcaga aaccgtgaga gagcccccac cgtggacacc ggctctaggg  93840 

ccacaggaaa aggaacgttt ccaggcattt tgtctccagg gctcccgctg gacaggcacg  93900 

tactgccctg gggagtaaat gcggagagtt cacgaactgt gcccaacgca tgttatagcc  93960 

agggtcctac taactactca gtaaaagaac gtattgttgt attcctccag tgttaagcta  94020 

tagccatgtt aaaagtcact gtgcatttat tctcagcatc aaataccttg taacgtcttc  94080 

tctgccttgt tagtgcatat ttttactttt ctgatactgt aaagaatata tccagtatgt  94140 

aaatgaatgt tctataaatc ttttgtatag tcattttctc tgctccttaa atatcatctc  94200 

tattcagagt ataataaaat tatgaacttg gtaagcctcc gtgagacggt atttgtgtac  94260 

cctgaagtat gtttgtgtgt gtttgcacat gtgtgtatgc gtgtgcatgt gtgcactttt  94320 

gtgtatgtgt ctctgcaaat gtgtgcatgt gcttgcacag atgtatcttt gtccacatgt  94380 

gtctgtgcgt ctgcgtgtgt gctcgttcat gaatgtgtgt ctgtgtgttt acaaatcagt  94440 

ggattcagtt ataaaatcac aaatgttttg ctgtcaggaa tatattaaga tttctgccca  94500 

gagacctttg aaatgttata ttcaaagatc tttgaagatt aaccacaatg cagtgttgat  94560 

aatgggtcct gacatgtttt cgatgttgct atgaataccc ctacacacac actggctgca  94620 

gaaacacacc cctgaagtgg gccagctcct gaaggacctc ccagtgtcta ttgaagtggg  94680 

cactaaaagt gaatattgag actggtggat tcacttacac atcaacagat gctggagaca  94740 

gccagtgtca cctgcctctt ctgttccccc agccaaggct cctccctccc caccttaagg  94800 

gagtttgccc ttttctacgg actctgccct cttgggcctg tcccctccct cctgagtcag  94860 

gtgatgggac acaggacccc atctaacctc actccctcag atccaaacca gaaaagaagc  94920 

aatgctttgg gctcatttgg ttatggacag ataaagatgg cagttagctg ccaccctgtg  94980 

cacagttttc tgcctgcgtg g                                            95001 

 
           
             12  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            12 

tcagcttcct gagtctcccg                                                 20 

 
           
             13  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            13 

agcatcgttg tcgtactgcc                                                 20 

 
           
             14  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            14 

ccatgcacat ttggagaagg                                                 20 

 
           
             15  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            15 

cctttcccca tgcacatttg                                                 20 

 
           
             16  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            16 

gggtcatcgt ctctttgacg                                                 20 

 
           
             17  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            17 

taaaattctg ccatcgataa                                                 20 

 
           
             18  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            18 

tctggagaca caggaaatgc                                                 20 

 
           
             19  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            19 

gctgttttca catacggtgt                                                 20 

 
           
             20  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            20 

gggcagcttc gtggttcacg                                                 20 

 
           
             21  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            21 

gcatcgtgga tttgggtccg                                                 20 

 
           
             22  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            22 

gcctgctgaa aggagggcgt                                                 20 

 
           
             23  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            23 

tggaaatggt gcaggaagaa                                                 20 

 
           
             24  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            24 

gtccttcctg gtaccggaga                                                 20 

 
           
             25  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            25 

gggacagctc atggctgtgg                                                 20 

 
           
             26  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            26 

agcaaggccc ccaggtcctc                                                 20 

 
           
             27  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            27 

ggacaggaag ccattgtcgg                                                 20 

 
           
             28  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            28 

tggtggctgc tgtgtccagg                                                 20 

 
           
             29  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            29 

ctgtgcgggc tggagaagcc                                                 20 

 
           
             30  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            30 

aggccgcttc tgaagccttg                                                 20 

 
           
             31  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            31 

atggcgatgg cttgttctct                                                 20 

 
           
             32  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            32 

cgagttcatt ggccaaatct                                                 20 

 
           
             33  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            33 

tatggttcat tcgagcaccc                                                 20 

 
           
             34  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            34 

cggcaaggcc aagggcgtga                                                 20 

 
           
             35  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            35 

tccaatggat ctctctctgg                                                 20 

 
           
             36  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            36 

ctccacagag ttcaagtacc                                                 20 

 
           
             37  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            37 

tgatgctcag ggccttctgg                                                 20 

 
           
             38  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            38 

ggtaatgcct ccggaagaag                                                 20 

 
           
             39  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            39 

catctttgat ccacttcctg                                                 20 

 
           
             40  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            40 

actggcaggc tgctcagggt                                                 20 

 
           
             41  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            41 

gggagttctc agaccttctt                                                 20 

 
           
             42  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            42 

acggctgtct ccagggcttc                                                 20 

 
           
             43  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            43 

tgtcagataa gtcactttca                                                 20 

 
           
             44  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            44 

gcttcttcta cccaaaaagc                                                 20 

 
           
             45  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            45 

atggcagtca ctcggcacct                                                 20 

 
           
             46  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            46 

gggtgcagct ggacagaagc                                                 20 

 
           
             47  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            47 

tacgccccct tctcagtttc                                                 20 

 
           
             48  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            48 

gggcctgact tgcacaaacc                                                 20 

 
           
             49  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            49 

ctaacgtggc caattcttcc                                                 20 

 
           
             50  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            50 

gaggcacaga gcactcacca                                                 20 

 
           
             51  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            51 

aggctgcagc atttgacact                                                 20 

 
           
             52  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            52 

cctgcggtgc atcctacata                                                 20 

 
           
             53  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            53 

cacagtccac tgcacactct                                                 20 

 
           
             54  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            54 

caatgagtaa aacatcaggg                                                 20 

 
           
             55  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            55 

gggaaaaaca ttccaatgag                                                 20 

 
           
             56  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            56 

gaagatgatc gaaaagccca                                                 20 

 
           
             57  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            57 

ccacacatgg tccccagcag                                                 20 

 
           
             58  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            58 

cactcaaaaa cagcttgtca                                                 20 

 
           
             59  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            59 

gtcacaaatt cccccaaacc                                                 20 

 
           
             60  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            60 

caggacagtc agcatgcctg                                                 20 

 
           
             61  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            61 

cagagttcac aaagcacatt                                                 20 

 
           
             62  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            62 

cactgtgatt tggctgcttc                                                 20 

 
           
             63  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            63 

aagtggaatg gtccacctgc                                                 20 

 
           
             64  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            64 

atgaggatct gctgaaaatg                                                 20 

 
           
             65  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            65 

ccgagatgct agaggcctct                                                 20 

 
           
             66  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            66 

gctctgactt ctaaatgagc                                                 20 

 
           
             67  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            67 

tggcaggctg cgtttctcaa                                                 20 

 
           
             68  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            68 

attccctggc aggctgcgtt                                                 20 

 
           
             69  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            69 

tcaaaaagca cgtttgcagg                                                 20 

 
           
             70  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            70 

ggagctatct gcttggagca                                                 20 

 
           
             71  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            71 

acgttccttt tcctgtggcc                                                 20 

 
           
             72  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            72 

tgaactctcc gcatttactc                                                 20 

 
           
             73  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            73 

ctggctataa catgcgttgg                                                 20 

 
           
             74  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            74 

aatacaacaa tacgttcttt                                                 20 

 
           
             75  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            75 

atggctatag cttaacactg                                                 20 

 
           
             76  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            76 

acagtgactt ttaacatggc                                                 20 

 
           
             77  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            77 

tgagaataaa tgcacagtga                                                 20 

 
           
             78  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            78 

atatattctt tacagtatca                                                 20 

 
           
             79  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            79 

tttatagaac attcatttac                                                 20 

 
           
             80  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            80 

atactctgaa tagagatgat                                                 20 

 
           
             81  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            81 

ccaagttcat aattttatta                                                 20 

 
           
             82  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            82 

ccttcagccc cactgaagta                                                 20 

 
           
             83  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            83 

tcattcttac catacggtgt                                                 20 

 
           
             84  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            84 

gatttcttac cacgtcctcc                                                 20 

 
           
             85  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            85 

tgctgaaaaa ctcctataca                                                 20 

 
           
             86  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            86 

ctttcactgc ctgatgccca                                                 20 

 
           
             87  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            87 

actaatgatg ttgaacatct                                                 20 

 
           
             88  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            88 

tttgatccac cttgcaaatt                                                 20 

 
           
             89  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            89 

tccaaagact ctgccaaagg                                                 20 

 
           
             90  
             20  
             DNA  
             H. sapiens  
             
 
           
            90 

cgggagactc aggaagctga                                                 20 

 
           
             91  
             20  
             DNA  
             H. sapiens  
             
 
           
            91 

ggcagtacga caacgatgct                                                 20 

 
           
             92  
             20  
             DNA  
             H. sapiens  
             
 
           
            92 

ccttctccaa atgtgcatgg                                                 20 

 
           
             93  
             20  
             DNA  
             H. sapiens  
             
 
           
            93 

ttatcgatgg cagaatttta                                                 20 

 
           
             94  
             20  
             DNA  
             H. sapiens  
             
 
           
            94 

cgtgaaccac gaagctgccc                                                 20 

 
           
             95  
             20  
             DNA  
             H. sapiens  
             
 
           
            95 

cggacccaaa tccacgatgc                                                 20 

 
           
             96  
             20  
             DNA  
             H. sapiens  
             
 
           
            96 

ttcttcctgc accatttcca                                                 20 

 
           
             97  
             20  
             DNA  
             H. sapiens  
             
 
           
            97 

tctccggtac caggaaggac                                                 20 

 
           
             98  
             20  
             DNA  
             H. sapiens  
             
 
           
            98 

ccacagccat gagctgtccc                                                 20 

 
           
             99  
             20  
             DNA  
             H. sapiens  
             
 
           
            99 

gaggacctgg gggccttgct                                                 20 

 
           
             100  
             20  
             DNA  
             H. sapiens  
             
 
           
            100 

cctggacaca gcagccacca                                                 20 

 
           
             101  
             20  
             DNA  
             H. sapiens  
             
 
           
            101 

ggcttctcca gcccgcacag                                                 20 

 
           
             102  
             20  
             DNA  
             H. sapiens  
             
 
           
            102 

caaggcttca gaagcggcct                                                 20 

 
           
             103  
             20  
             DNA  
             H. sapiens  
             
 
           
            103 

agatttggcc aatgaactcg                                                 20 

 
           
             104  
             20  
             DNA  
             H. sapiens  
             
 
           
            104 

gggtgctcga atgaaccata                                                 20 

 
           
             105  
             20  
             DNA  
             H. sapiens  
             
 
           
            105 

tcacgccctt ggccttgccg                                                 20 

 
           
             106  
             20  
             DNA  
             H. sapiens  
             
 
           
            106 

ccagagagag atccattgga                                                 20 

 
           
             107  
             20  
             DNA  
             H. sapiens  
             
 
           
            107 

ggtacttgaa ctctgtggag                                                 20 

 
           
             108  
             20  
             DNA  
             H. sapiens  
             
 
           
            108 

ccagaaggcc ctgagcatca                                                 20 

 
           
             109  
             20  
             DNA  
             H. sapiens  
             
 
           
            109 

accctgagca gcctgccagt                                                 20 

 
           
             110  
             20  
             DNA  
             H. sapiens  
             
 
           
            110 

aagaaggtct gagaactccc                                                 20 

 
           
             111  
             20  
             DNA  
             H. sapiens  
             
 
           
            111 

gaagccctgg agacagccgt                                                 20 

 
           
             112  
             20  
             DNA  
             H. sapiens  
             
 
           
            112 

tgaaagtgac ttatctgaca                                                 20 

 
           
             113  
             20  
             DNA  
             H. sapiens  
             
 
           
            113 

gctttttggg tagaagaagc                                                 20 

 
           
             114  
             20  
             DNA  
             H. sapiens  
             
 
           
            114 

aggtgccgag tgactgccat                                                 20 

 
           
             115  
             20  
             DNA  
             H. sapiens  
             
 
           
            115 

gcttctgtcc agctgcaccc                                                 20 

 
           
             116  
             20  
             DNA  
             H. sapiens  
             
 
           
            116 

gaaactgaga agggggcgta                                                 20 

 
           
             117  
             20  
             DNA  
             H. sapiens  
             
 
           
            117 

ggtttgtgca agtcaggccc                                                 20 

 
           
             118  
             20  
             DNA  
             H. sapiens  
             
 
           
            118 

ggaagaattg gccacgttag                                                 20 

 
           
             119  
             20  
             DNA  
             H. sapiens  
             
 
           
            119 

tggtgagtgc tctgtgcctc                                                 20 

 
           
             120  
             20  
             DNA  
             H. sapiens  
             
 
           
            120 

agtgtcaaat gctgcagcct                                                 20 

 
           
             121  
             20  
             DNA  
             H. sapiens  
             
 
           
            121 

tatgtaggat gcaccgcagg                                                 20 

 
           
             122  
             20  
             DNA  
             H. sapiens  
             
 
           
            122 

ccctgatgtt ttactcattg                                                 20 

 
           
             123  
             20  
             DNA  
             H. sapiens  
             
 
           
            123 

ctcattggaa tgtttttccc                                                 20 

 
           
             124  
             20  
             DNA  
             H. sapiens  
             
 
           
            124 

tgggcttttc gatcatcttc                                                 20 

 
           
             125  
             20  
             DNA  
             H. sapiens  
             
 
           
            125 

ctgctgggga ccatgtgtgg                                                 20 

 
           
             126  
             20  
             DNA  
             H. sapiens  
             
 
           
            126 

tgacaagctg tttttgagtg                                                 20 

 
           
             127  
             20  
             DNA  
             H. sapiens  
             
 
           
            127 

ggtttggggg aatttgtgac                                                 20 

 
           
             128  
             20  
             DNA  
             H. sapiens  
             
 
           
            128 

caggcatgct gactgtcctg                                                 20 

 
           
             129  
             20  
             DNA  
             H. sapiens  
             
 
           
            129 

gaagcagcca aatcacagtg                                                 20 

 
           
             130  
             20  
             DNA  
             H. sapiens  
             
 
           
            130 

gcaggtggac cattccactt                                                 20 

 
           
             131  
             20  
             DNA  
             H. sapiens  
             
 
           
            131 

cattttcagc agatcctcat                                                 20 

 
           
             132  
             20  
             DNA  
             H. sapiens  
             
 
           
            132 

agaggcctct agcatctcgg                                                 20 

 
           
             133  
             20  
             DNA  
             H. sapiens  
             
 
           
            133 

gctcatttag aagtcagagc                                                 20 

 
           
             134  
             20  
             DNA  
             H. sapiens  
             
 
           
            134 

ttgagaaacg cagcctgcca                                                 20 

 
           
             135  
             20  
             DNA  
             H. sapiens  
             
 
           
            135 

aacgcagcct gccagggaat                                                 20 

 
           
             136  
             20  
             DNA  
             H. sapiens  
             
 
           
            136 

cctgcaaacg tgctttttga                                                 20 

 
           
             137  
             20  
             DNA  
             H. sapiens  
             
 
           
            137 

tgctccaagc agatagctcc                                                 20 

 
           
             138  
             20  
             DNA  
             H. sapiens  
             
 
           
            138 

ggccacagga aaaggaacgt                                                 20 

 
           
             139  
             20  
             DNA  
             H. sapiens  
             
 
           
            139 

ccaacgcatg ttatagccag                                                 20 

 
           
             140  
             20  
             DNA  
             H. sapiens  
             
 
           
            140 

cagtgttaag ctatagccat                                                 20 

 
           
             141  
             20  
             DNA  
             H. sapiens  
             
 
           
            141 

gccatgttaa aagtcactgt                                                 20 

 
           
             142  
             20  
             DNA  
             H. sapiens  
             
 
           
            142 

tcactgtgca tttattctca                                                 20 

 
           
             143  
             20  
             DNA  
             H. sapiens  
             
 
           
            143 

tgatactgta aagaatatat                                                 20 

 
           
             144  
             20  
             DNA  
             H. sapiens  
             
 
           
            144 

atcatctcta ttcagagtat                                                 20 

 
           
             145  
             20  
             DNA  
             H. sapiens  
             
 
           
            145 

tacttcagtg gggctgaagg                                                 20 

 
           
             146  
             20  
             DNA  
             H. sapiens  
             
 
           
            146 

tgtataggag tttttcagca                                                 20 

 
           
             147  
             20  
             DNA  
             H. sapiens  
             
 
           
            147 

tgggcatcag gcagtgaaag                                                 20 

 
           
             148  
             20  
             DNA  
             H. sapiens  
             
 
           
            148 

agatgttcaa catcattagt                                                 20 

 
           
             149  
             20  
             DNA  
             H. sapiens  
             
 
           
            149 

cctttggcag agtctttgga                                                 20