Patent Publication Number: US-2023144739-A1

Title: Treatment of covid-19 with reverse micelle system comprising unmodified oligonucleotides

Description:
FIELD OF THE INVENTION 
     The present invention relates to specific reverse micelle system of the invention which allows the administration and intracellular delivery of unmodified oligonucleotide, such as siRNA, targeting one or more genes of the SARS-CoV-2 virus. The reverse micelle system of the invention is thus particularly useful for the treatment of the viral pathology linked to the SARS-CoV-2 virus. 
     BACKGROUND OF THE INVENTION 
     Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has spread globally since 2019, resulting in the 2019-21 coronavirus pandemic. Common symptoms include fever, cough and shortness of breath. 
     Muscle pain, sputum production and sore throat are less common symptoms. While the majority of cases result in mild symptoms, some progress to pneumonia and multi-organ failure. The deaths per number of diagnosed cases is estimated at between 1% and 5% but varies by age and other health conditions. 
     There is consequently a major public health emergency to treat CoVID_19 which is spreading worldwide very quickly. 
     RNAi (RNA interference) and antisense (AS) strategies consist in silencing the expression of a target gene by the use of nucleic acids which allow the degradation or the translational arrest of mRNA target. New antisense applications (exon skipping, alternative splicing correction), by masking the mutation responsible for an alternative splicing default, have permitted the synthesis of a functional protein. Aptamers are nucleic acids capable of interacting with a target protein and down regulating its synthesis. The discovery of all these nucleic acids, and more recently siRNA and miRNA, has opened wide perspectives in therapeutics for the treatment of diseases like genetic diseases, cancers, neurodegenerative diseases, infectious and inflammatory diseases or to block cell proliferation and diseases caused thereby. 
     However, these molecules are unstable in biological fluids, in vitro and in vivo, they display a poor intracellular penetration and low bioavailability. These critical drawbacks have limited their use in therapeutics. As a result, clinical applications of said nucleic acids have required chemical modifications with the aim of retaining their capacity to knockdown protein expression while increasing stability and cellular penetration. Research groups have also applied the nanotechnology approach to improve their delivery, to overcome most barriers that hampered the development of nucleic acids delivery-based therapies. To improve bioavailability, many researchers have also attempted to use alternative administration routes: ocular, skin, oral, intramuscular. Those attempts have not been totally satisfactory so far. For instance, some of these attempts, more specifically assays with nucleic acids in liposome carriers have stimulated immune response. 
     The object of the present invention is to overcome disadvantages of the prior art. There is an obvious need for a safe and efficient nucleic acids therapeutic strategy for the treatment of diseases related to SARS-CoV-2 virus (or for the treatment of COVID-19), and in particular for new tools that are able to achieve efficient gene expression modulation-based therapy in order to treat diseases related to SARS-CoV-2 virus. More particularly, it is an object of the invention to provide a drug delivery system comprising an unmodified oligonucleotide targeting one or more genes of SARS-CoV-2, which can be for instance administered via buccal mucosa, giving rise to a satisfactory drug bioavailability in an active form. 
     SUMMARY OF THE INVENTION 
     The present invention relates to a delivery system for the in vivo, or ex vivo release of unmodified oligonucleotides targeting SARS-CoV-2 RNAs, by administration to the buccal or rectal mucosa of said delivery system, as well as the compositions and methods for preparing the delivery system. 
     More specifically, the delivery system is a reverse micelle system comprising at least one sterol, acylglycerol, phospholipid, an alcohol, and at least one unmodified oligonucleotide targeting one or more genes of SARS-CoV-2 virus. 
     Herein described are reverse micelle systems designed to reach this goal in a safe and controlled manner. 
     The reverse micelle systems are able to be absorbed through mucosa and to vectorize unmodified oligonucleotides under a protected form to all cells of any tissue of the organism. The invention also relates to a pharmaceutical composition comprising a reverse micelle system as defined herein and a pharmacologically acceptable support or carrier. 
     The present invention relates to the use of unmodified oligonucleotides targeting CoV_2019 RNAs, in particular siRNAs whose sequences have been designed to inhibit one or more genes expression of this virus, in the preparation of reverse micelle systems or pharmaceutical compositions comprising the same in the treatment of diseases related to SARS-CoV-2 (or in the treatment of COVID-19). 
     The aim of the present invention is to provide unmodified oligonucleotides targeting SARS-CoV-2 RNAs in a delivery system that allows to vectorize said oligonucleotides as to down regulate or knock down the expression of a target nucleic acid of SARS-CoV-2 virus, with high efficiency and limited off-target-mediated secondary effects. 
     Drug delivery technology according to the invention allows intracellular delivery to all tissues and organs using HDL lipoprotein (High Density Lipoprotein) or vHDL lipoprotein (Very-High-Density Lipoprotein) receptors. 
     More particularly, the present invention provides a reverse-micelle transport system for delivering unmodified oligonucleotides capable of modulation of gene expression or duplication of genes of SARS-CoV-2 virus. More specifically, reverse micelles according to the invention allow the incorporation thereof in HDL and vHDL lipoprotein in the buccal or rectal mucosa. Reverse micelles according to the invention are thus carried in a protected lymphatic transport form, then in the general blood circulation which finally allows an intracellular delivery of said oligonucleotides by the membrane receptors of HDL lipoproteins, of the SRB-1 type (Scavenger receptor class B type 1). 
     Advantageously, at no time can the subject&#39;s immune system detect the presence of the oligonucleotide, with absence of immune reaction when unmodified oligonucleotides are administered in the technology according to the invention. 
     The reverse micelles can be prepared according to a method described below using at least a sterol, an acylglycerol, a phospholipid, an alcohol, water, and at least one unmodified oligonucleotide targeting one or more genes of SARS-CoV-2 virus. 
     Said micelles are more particularly obtainable by the following method:
         (a) Contacting (i) sterol, preferably sitosterol or cholesterol, (ii) acylglycerol, preferably diacylglycerol of fatty acids, (iii) phospholipid, preferably phosphatidylcholine, (iv) alcohol, (v) water, preferably purified water, and (vi) at least an unmodified oligonucleotide targeting one or more genes of SARS-CoV-2 virus,   (b) Stirring mixture obtained in step (a), at 40° C. or less, and for a time sufficient to obtain formation of reverse micelles, said stirring being preferably carried out mechanically or by sonication.       

     The parameters of the mechanical stirring, for instance duration and speed, can be readily determined by anyone skilled in the art and depend on experimental conditions. In practice, these parameters are such that a micro-emulsion is obtained; the speed is determined so as to enable formation of a visually transparent formulation, and duration of the stirring is such that the stirring may be stopped a few minutes after obtaining the visually transparent formulation. 
     The present invention further relates to a pharmaceutical composition comprising reverse micelles of the invention and a pharmaceutically acceptable carrier, excipient or support. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following description is of preferred embodiments by way of examples only and without limitation to the combination of features necessary for implementing the invention. 
     Reverse Micelles 
     The reverse micelle system according to the invention is characterized as a micro-emulsion comprising a dispersion of water-nanodroplets in oil. The dispersion is stabilised by two surfactants (acylglycerol, more preferably a diacylglycerol of fatty acids and a phospholipid, more preferably phosphatidylcholine) and a co-surfactant (alcohol) that are most likely at the water/oil interface. The reverse micelle phase can be defined as a system wherein water forms the internal phase and the hydrophobic tails of the lipids form the continuous phase. Reverse micelles containing oil(s), surfactant(s), co-surfactant(s), and an aqueous phase are also characterized as water-in-oil micro-emulsions. 
     Generally, the size of micelles according to the invention is very small, more particularly, it is less than 10 nm; more specifically it is less than 8 nm and more preferably less than 5 nm. The size may vary with the quantity of added water and phospholipid. The present invention relates more particularly to reverse micelles with an aqueous core of 3 to 5 nm, preferably from 3.5 to 5 nm, in particular from 3.7 to 4.5 nm. 
     The reverse micelles and the size of their aqueous core can be characterized by various methods, including:
         Small Angle X-Ray Scattering (SAXS)   Neutrons Scattering   Transmission Electron Microscopy (TEM)   Dynamic Light Scattering (DLS)       

     The ratios of the lipidic constituents (including sterol, acylglycerol and phospholipid) in the reverse-micelle system according to the invention can vary. For instance, the weight ratio sterol/acylglycerol can range from 0.015 to 0.05, more particularly from 0.03 to 0.04. The weight ratio phospholipid/acylglycerol is from 0.06 to 0.25. For the calculation of these ratios, the weight of phospholipid corresponds to the total weight of the mixture of phospholipids, for instance the weight of lecithin, used in the formulation. 
     The compounds of the reverse-micelle system can be analysed by appropriate means. More specifically, sterols can be identified by gas chromatographic analysis and acylglycerol by high-performance liquid chromatography (HPLC), in particular with a light scattering detector, on a silica column (kromasil C18), in the presence of an eluent, e.g. isocratic acetonitrile. Gas chromatography can also be used to analyse diacylglycerols. Phospholipids can be analysed by high-performance liquid chromatography (HPLC), with a diol column with a light scattering detector. 
     Reverse micelles are dynamic systems. Brownian motion causes perpetual collisions of micelles, which lead to coalescence of micelles and exchange of the aqueous cores. Separation and regeneration of micelles occur and allow chemical reactions between different solutions. The exchange rate between micelles increases in particular with temperature, the length of hydrocarbon chains of the surfactant, and the water/surfactant ratio. Within the context of the invention and contrary to what is expected in nanotechnology, aqueous cores of micelles must have a specific size allowing one or more molecules of unmodified oligonucleotide, in particular nucleic acid capable of mediating RNA interference, to be stabilised in the prepared micelles. As mentioned above, the size of the aqueous core is around 4 nm, preferably from 3 to 5 nm, more preferably from 3.5 to 5 nm, in particular from 3.7 to 4.5 nm. 
     Without being bound to any theory, it seems that inclusion of a phospholipid in the reverse micelle system allows formation of micelles with greater diameter and volume, thus allowing vectorization of greater quantities of oligonucleotide. 
     In addition, it seems that, when applied to mucosa tissue, the reverse micelle system triggers formation of lipoproteins which after a lymphatic transport then in the blood circulation cross the cellular membrane and allow delivery of the oligonucleotide, in particular the nucleic acid capable of modulating gene expression of SARS-CoV-2 virus into the cells. 
     After the deposition of the micro emulsion on the buccal mucosa (or rectal mucosa) in the subject, the Brownian dynamics of the reverse micelles promotes intramucosal penetration into the intercellular spaces, and in contact with the apoproteins present physiologically in the mucosa, there takes place a structure in lipoproteins vHDL and HDL. 
     Oligonucleotides must be soluble in water, so as not to interfere with the water/oil interface of the reverse micelles according to the invention. 
     An amphiphilic molecule modifies the water solubility in the nano micelles, interferes with the interface and removes the fluidity of the permanent Brownian-like motions of the micelles which is necessary for their passage in the mucosa and their absorption through the structuration in lipoproteins. 
     The oligonucleotides described in the present invention are necessarily unmodified in order to be water-soluble. 
     Accordingly, the invention ensures absorption of the compounds to be delivered across mucosa, preferably across mouth, nasal and/or rectal mucosa, more preferably across mouth mucosa. Also, reverse micelles of the present invention provide an important bioavailability with low variability of absorption. 
     Method for Preparing Reverse Micelles 
     In a particular embodiment, the invention relates to a method for preparing reverse micelles as defined above (involving more specifically at least one unmodified oligonucleotide targeting one or more genes of SARS-CoV-2 virus, a sterol, an acylglycerol, a phospholipid, an alcohol, and water), wherein said method comprises the following steps:
         (a) Contacting (i) sterol, (ii) acylglycerol, preferably diacylglycerol of fatty acids, (iii) phospholipid, preferably phosphatidylcholine, (iv) alcohol, (v) water, preferably purified water, and (vi) at least one unmodified oligonucleotide capable of targeting one or more genes of SARS-CoV-2 virus,   (b) Stirring mixture obtained in step (a), at 40° C. or less, and for a time sufficient to obtain formation of reverse micelles, said stirring being carried out mechanically or by sonication.       

     The obtained and recovered reverse micelles are then particularly useful as a delivery system for unmodified oligonucleotides. Step (b) of the process is of particular importance since it allows reverse micelles to be obtained, said reverse micelles being then useful as a transport system to deliver unmodified oligonucleotides directly into the cytoplasm of all cells in all tissues and organs, through the cell membrane lipoprotein receptors. 
     In a particular embodiment, the unmodified oligonucleotide is first solubilised in water (preferably purified water) to form an aqueous phase. Said aqueous phase is then introduced into the oily phase (according to step(a)). The oily phase preferably comprises at least a sterol, an acylglycerol, a phospholipid and an alcohol. 
     The compounds involved in step (a) will be described in more details below. 
     Stirring of the mixture obtained by step (a) is carried out at a temperature less than or equal to 40° C., preferably ranging from 30° C. to 38° C., more preferably from 30° C. to 35° C., for a time sufficient to form of reverse micelles. The time sufficient can vary in particular upon the used stirring techniques, i.e., mechanical stirring or sonication. The time of mechanical stirring or sonication is more specifically the time needed to convert the initial mixture into a visually transparent reverse micelle solution. 
     One skilled in the art knows how to select excipients or components that may be used along with the composition according to the present invention in order to keep their beneficial properties. In particular, the presence of glycerol can, when introduced in large amount, prevent the formation of reverse micelles or break the reverse micelle system. More specifically, no more than 2.5%, and preferably no glycerol (percent expressed by weight of glycerol/weight of acylglycerol) is used for the preparation of the reverse micelles of the present invention. 
     Other compounds can be introduced in step (a). One can cite for instance colouring agents and/or flavouring substances. 
     In an advantageous manner, the compounds cited above or the commercially available mixtures containing them are the only ingredients introduced to prepare the micelle system and consequently the only ones present in the micelle system of the invention. 
     Physical parameters, in particular time—for instance comprised between 3 and 5 minutes, in one or several times-, are dependent on the used material, volumes of the mixture and viscosity thereof. One skilled in the art can readily define such parameters. Temperature of the mixture is less than 40° C. Such a temperature avoids degradation of the reactants. Temperature is preferably ranging from 30° C. to 38° C., more preferably from 30° C. to 35° C. 
     The usual materials use propellers whose fast movements generate turbulences and swirls allowing interpenetration of particles and formation of reverse micelles within the mixture. 
     Stirring speed is preferably ranging from 200 to 2 000 r/minute, more preferably from 300 to 700 r/minute. The implemented volumes, device, and stirring speed depend on and should be adapted with the reactants and amounts thereof. 
     As described above, temperature of the mixture must not exceed 40° C. Temperature is preferably ranging from 30° C. to 38° C., more preferably from 30° C. to 35° C. 
     Reverse Micelles Compounds 
     Acylglycerol 
     Acylglycerols, more particularly acylglycerols of fatty acids, useful for the preparation of the reverse-micelle system according to the invention can be isolated from the majority of animals and more preferably plants. 
     Acylglycerols can be mono- and/or diacylglycerols. In a particular embodiment, mono- or diacylglycerols preferentially used in the present invention present the following formula (I): 
     
       
         
         
             
             
         
       
     
     in which:
         R 1  is an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 14 and 24 carbon atoms, a hydrogen atom, or a mono-, di- or tri-galactose or glucose;   R 2  is an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 2 and 18 carbon atoms;   R 3  is an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 14 and 24 carbon atoms, or a hydrogen atom.       

     According to a particular embodiment, R 1  or R 3 , preferably only one of R 1  and R 3 , in particular only R 1 , represents an acyl residue of oleic acid (C18: 1[cis]-9), including in particular glycerol monooleate. 
     According to a particular aspect, R 2  has one unsaturated bond (e.g; ethylenic bond) and has advantageously 18 carbon atoms, preferably R 2  is an oleic acid residue (oleoyl group), one of its positional isomers with respect to the double bond (cis-6,7,9,11 and 13) or one of its iso-branched isomers. 
     According to another particular aspect, R 1  represents an oleoyl group. 
     According to another particular aspect, R 2  represents an acetyl group. 
     According to another particular aspect, R 3  is a hydrogen atom. 
     As a general rule, oil containing a high concentration of oleic acid will be chosen as a useful source of acylglycerols according to the invention. Such oil usually contains a high proportion of acylglycerols useful according to the invention. 
     According to a particular aspect of the invention, the preferred diglycerols of fatty acids are selected in the group consisting of 1,2-diolein and 1-oleoyl-2-acetyl glycerol. 
     A certain number of them, and more particularly those which are found to be the most active in the applications sought after, are also available commercially. This is the case particularly for 1-oleoyl-2-acetylglycerol and 1,2-dioleoylglycerol, which exist as commercial products with a high purity content. In particular, glycerol monooleate containing about 44% of dioleic glycerol, from which about 14% is 1,2-diolein. Such a compound is pharmaceutically accepted ( European Pharmacopeia  (4 th  Edition), USP 25/NF20, and  Japanese Standard of food Additives ). Such product is for instance commercially available by Gattefossé Company under the name PECEOL®. 
     The acylglycerols are preferably incorporated or comprised in the composition or reverse-micelle system in an amount by weight ranging from 55 g to 90 g with respect to 100 g of the total weight of the composition or reverse-micelle system according to the invention. 
     Sterols 
     The sterols useful for the preparation of the reverse-micelle system according to the invention are preferably natural sterols, such as cholesterol or phytosterols (vegetable sterols). Sitosterol or cholesterol are the preferred sterols useful for the reverse-micelle system according to the invention. 
     Sitosterol and cholesterol are commercially available. More particularly, commercial sitosterol which is extracted from soya can be used. In such a product, the sitosterol generally represents from 50 to 70% by weight of the product and is generally found in a mixture with campesterol and sitostanol in respective proportions in the order of 15% each. Commercial sitosterol which is extracted from a variety of pine called tall oil can also be used. In general, it will be possible to use sitosterol in mixture with sitostanol. Preferably, said mixture comprises at least 50% sitosterol by weight of the mixture. 
     As mentioned above, the ratios of the lipidic constituents (sterols, acylglycerol and phospholipids) in the reverse-micelle system according to the invention can vary in a wide range, for instance the weight ratio sterols/acylglycerol can range from 0.015 to 0.05, more particularly from 0.03 to 0.04. 
     Phospholipids 
     Phospholipids are formed of a glycerol linked to 2 fatty acids and to a phosphate group. The variability of phospholipids relies on the fatty acids that are attached to the glycerol and on the chemical groups that are susceptible to link to the phosphate group. Phospholipids are the major lipidic constituents of biological membranes. 
     Among phospholipids useful in the present invention may be cited phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine. 
     In a particular embodiment, the phospholipid is phosphatidylcholine. Phosphatidylcholine is also known as 1,2-diacyl-glycero-3-phosphocholine or PtdCho. 
     Phosphatidylcholine is formed from a choline, a phosphate group, a glycerol and two fatty acids. It is actually a group of molecules, wherein the fatty acid compositions vary from one molecule to another. Phosphatidylcholine may be obtained from commercial lecithin that contains phosphatidylcholine in concentrations of 20 to 98%. The lecithin preferably used for the preparation of the reverse micelles according to the invention is Epikuron 200® and contains phosphatidylcholine at a concentration of more than 90%. 
     The weight ratio phospholipid/acylglycerol in compositions or reverse-micelle systems according to the invention is from 0.06 to 0.30. 
     Alcohols 
     The alcohols useful for the preparation of the reverse-micelle system according to the invention are preferably linear or branched mono-alcohols from C2 to C6. Examples of alcohols are ethanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol and any mixture thereof. In a particular embodiment of the invention, alcohol is ethanol. 
     The alcohol is preferably incorporated or comprised in the composition or reverse-micelle system in an amount by weight ranging from 5 g to 17 g with respect to 100 g of the total weight of the composition or reverse-micelle system according to the invention. 
     Oligonucleotides 
     The unmodified oligonucleotides targeting SARS-CoV-2 RNAs or targeting one or more genes of SARS-CoV-2 virus can be any nucleic acid molecule capable of modulating gene expression by down regulating or knocking down the expression of a target nucleic acid sequence of SARS-CoV-2 virus. 
     Down regulating or knocking down the expression of a target nucleic acid sequence can be commonly accomplished via RNA interference (RNAi). RNAi generally designates a phenomenon by which dsRNA specifically reduces expression of a target gene at post-translational level. In normal conditions. RNA interference is initiated by double-stranded RNA molecules (dsRNA) of various length, for example ranging from 15 to 30 base pair length. In vivo, dsRNA introduced into a cell is cleaved into a mixture of short dsRNA molecules. 
     Nucleic acid molecules capable of modulating gene expression by down regulating or knocking down the expression of a target nucleic acid sequence SARS-CoV-2 virus can thus include “antisense oligonucleotides”, “short interfering nucleic acid” (siNA), “short interfering RNA” (siRNA), “short interfering nucleic acid molecule”, “short interfering oligonucleotide molecule”, “miRNA”, “micro RNA”, guide RNA (gRNA), short guide RNA (sgRNA) of a CRISPR system, “short hairpin RNA” (shRNA) or a mixture thereof. 
     Unmodified oligonucleotides as defined above, such as unmodified siRNAs, are prone to rapid degradation by ubiquitous endo- and exonucleases and they are generally undetectable in the blood already 10 min after administration. 
     The oligonucleotides used in the present invention are necessarily chemically unmodified in order to be perfectly water-soluble. More specifically, unmodified oligonucleotides refer to oligonucleotides without any structural modifications at the ribose level (e.g. 2′-fluoro, 2′-methyl, and/or 2′-methoxy), at the base level and at the backbone level (e.g. phosphodiester, phosphorithioate). 
     According to a preferred embodiment, oligonucleotides of the present invention are at least 10, 15, 20 or 25 nucleotides (nt) long, more preferably in the range of 19 to 25 nucleotides long, or typically 19, 20, 21, 22, 23, 24 or 25 nt long. 
     According to a preferred embodiment, oligonucleotides of the present invention are designed to have complementarity to the target sequence. In the context of the present invention, they are more specifically designed to have complementarity to a target nucleic acid sequence of the SARS-CoV-2 virus genome. Said viral genome is for instance as described by SEQ ID NO 7. 
     The term RNA interference (RNAi) is used to describe gene silencing or knocking down at the mRNA level guided by small complementary non-coding RNA species. There are several classes of RNAi mediators, one of which, namely small interfering RNAs (siRNAs). The source of siRNAs during infection is viral double-stranded RNA (dsRNA), which is cleaved by cytoplasmic RNAse III family enzyme Dicer into 19-27 base pair (bp) long molecules with a perfectly complementary middle region and 2-nt overhangs on both 3′ ends. These siRNAs are incorporated into a multiprotein RNA-induced silencing complex (RISC). Following the strand separation, the antisense strand (i.e. guide strand) guides the RISC to recognize and cut target RNA transcripts (the other strand is called passenger strand). 
     Unmodified oligonucleotides as defined above, such as unmodified siRNAs, are aimed at inhibiting or reducing contagiousness of SARS-CoV-2 virus, more specifically, by protecting host from viral infection, inhibiting the expression of viral antigen or accessory genes, controlling the transcription, retro transcription or replication of viral genome, hindering the assembly of viral particles, or displaying influences in virus-host interactions. 
     Unmodified oligonucleotides as defined above, such as unmodified siRNAs, can thus be used to protect host from viral infection, inhibit the expression of viral antigen and accessory genes, control the transcription, retro transcription or replication of viral genome, hinder the assembly of viral particles, or display influences in virus-host interactions. 
     Whether RNAi is a functional antiviral pathway in mammals is still contentious, since production of siRNA molecules from long dsRNAs cannot be explicitly demonstrated in mammalian cells due to the fact that dsRNA longer than 30 bp triggers activation of interferon (IFN) response which shuts down the natural RNAi. However, mammalian cells do possess all the components of evolutionary conserved RNAi machinery that can be harnessed to inhibit the expression of cognate mRNA by exogenous siRNA molecules. The antiviral potential of siRNAs was first demonstrated against respiratory syncytial virus and thereafter numerous studies describing antiviral activity of siRNAs against viruses with DNA and RNA genomes in vitro and in vivo have been published. RNAi-based drugs thus appear to be a viable option to treat severe viral infections, against which effective vaccines or specific cure is not available yet, such as Ebola virus or emerging viruses, in particular SARS-CoV-2 virus. 
     The first step in production of antiviral siRNAs is in silico selection of highly conservative sequences in the targeted virus genome in order to achieve strong antiviral activity and avoid off-target effects. 
     After internalization of siRNA duplexes in treated cells, the duplexes are loaded on proteins of the “Ago” family, forming a molecular complex named “RISC” (RNA-induced silencing complex). There are 4 Ago proteins in mouse and in human, but only one (called “Ago2”) is able to degrade target RNAs by endonucleolytic cleavage. That reaction generally occurs when the guide strand and the target are highly complementary (a perfect match to the “seed” [preferably nucleotides 2-7 of the guide strand] is important for target binding; and a perfect match to the central part [preferably nucleotides 8-14] of the guide strand is important for target cleavage). 
     According to a preferred embodiment, oligonucleotides of the present invention are designed to have complementarity to a target nucleic acid sequence of SARS-CoV-2 virus genome (such as SEQ ID NO 7). This complementarity involves at least 13 bases, typically between 13 and 25 bases, preferably at least 14 bases, even more preferably at least 18 bases of the oligonucleotides of the present invention. 
     The term “complementary” or “complementarity” refers herein to the ability of oligonucleotides to form base pairs with another nucleotide molecule. Base pairs are typically formed by hydrogen bonds between nucleotide units in antiparallel polynucleotide strands. Complementary polynucleotide strands can base pair in the Watson-Crick manner (e.g., A to T, A to U, C to G), or in any other manner that allows for the formation of duplexes. As persons skilled in the art are aware, when using RNA as opposed to DNA, uracil rather than thymine is the base that is considered to be complementary to adenosine. However, when a U is denoted in the context of the present invention, the ability to substitute a T is implied, unless otherwise stated. Perfect complementarity or 100 percent complementarity refers to the situation in which each nucleotide unit of the oligonucleotide strand of the invention can bind to a nucleotide unit of a second oligonucleotide strand. Less than perfect complementarity refers to the situation in which some, but not all, nucleotide units of two strands can bind with each other. For example, for two 20-mers, if only two base pairs on one strand of the invention (e.g. guide strand) can bind with the other, the oligonucleotide strand of the invention exhibits 10 percent complementarity. In the same way, if 20 base units of one 20 nt strand (e.g. guide strand) can be bond with 20 other base units of the target gene, the oligonucleotide strands of the invention exhibit 100 percent complementarity. 
     In a particular aspect, the oligonucleotides of the present invention is a RNA, typically a double-stranded RNA (or RNA duplexes), in particular a small interfering RNA (siRNA), with a guide strand and a passenger strand. 
     According to a more particular embodiment, the oligonucleotides of the present invention are synthetic RNA duplexes comprising or consisting of two unmodified 21-mer oligonucleotides annealed together to form short/small interfering RNAs (siRNAs). 
     The main limitation of anti-viral RNAi is the great mutability of viruses. It can be anticipated that siRNA-resistant virus variants will emerge rapidly. In order to delay as much as possible, the emergence of such variants, it is better to target constant regions of the virus genome (i.e.: regions that are exactly identical among the sequenced variants of the virus). 
     According to a particular embodiment, the unmodified oligonucleotide targeting one or more genes of the virus SARS-CoV-2 targets constant regions of the virus genome. 
     mRNA accessibility to RISC can be hindered by RNA-binding proteins, whose binding pattern is not known. But the 5′ UTR and coding sequence of mRNAs are cleaned by ribosome scanning making them more sensitive to RISC than the 3′ UTR: while scoring predicted off-targets, it is advisable to focus on those with a seed match in their 3′ UTR. 
     According to a particular embodiment, the unmodified oligonucleotide targeting one or more genes of the virus SARS-CoV-2 targets the 5′ UTR and coding sequence of the virus genome. 
     mRNA accessibility to RISC can also be inhibited by mRNA secondary structures, especially short-term interactions, which are likely to re-form rapidly after ribosome scanning. 
     According to a particular embodiment, the unmodified oligonucleotide targeting one or more genes of the virus SARS-CoV-2 targets poorly-structured regions of the mRNA of SARS-CoV-2 virus. 
     Natural human miRNAs frequently have a 5′ uridine, which may be due to an intrinsically higher affinity of the Ago protein or its loading machinery (at least Ago2 binds preferentially 5′ uridines and 5′ adenosines). 
     According to a particular embodiment, the unmodified oligonucleotide targeting one or more genes of SARS-CoV-2 virus, and in particular its guide strand, has a 5′ uridine base. 
     In addition to the intended target, introduced siRNAs might bind additional mRNAs (“off-targets”). The main determinant of target recognition is a perfect match between nucleotides 2-7 of the guide strand (the “seed” of the guide strand) and the off-target RNA. If there are many off-targets, the siRNA is likely to be partially titrated, hence less efficient. And because off-targets might be (moderately) repressed by the siRNA, they could trigger unwanted secondary effects. It is thus preferable to choose siRNAs that minimize the number of off-targets, and to minimize the number of off-targets whose modest down-regulation is most susceptible to trigger phenotypic consequences in humans. 
     The SARS-CoV-2 virus has an RNA genome, so it is theoretically possible to target both the genomic RNA (which is about 30 kb long) and individual mRNAs (there are 9 annotated ORFs—open reading frames—in the SARS-CoV-2 genome). mRNAs are more likely to be accessible to siRNAs, because genomic RNA is largely protected by encapsidation. 
     According to a particular embodiment, the unmodified oligonucleotide targeting one or more genes of SARS-CoV-2 targets one or more viral sequences that belong to mature mRNAs of SARS-CoV-2. 
     According to a particular embodiment, the unmodified oligonucleotide of the invention targets the mRNA of the longest protein produced by the virus. The function of this protein is not yet known with precision; in the viral genome, its gene is called “ORFlab”. Said gene extends from position 266 to position 21555 of the viral genome shown in SEQ ID NO 7, and siRNA of the invention more preferably targets the region between positions 14790 to 14810 of said genome. 
     Up to date, these positions of the viral genome are, at the same time, 100% conserved between all the sequenced variants of the virus genome (more than one thousand variants described to date) and they are particularly accessible to siRNAs. (little folded in on themselves). 
     According to a particular embodiment, the siRNA of the invention presents a guide strand which comprises, or consists of, one of the following sequences: 
     
       
         
           
               
               
            
               
                   
                 SEQ ID NO 1: 
               
               
                   
                 5′ P-UGAUAGUAGUCAUAAUCGCUA 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 3: 
               
               
                   
                 5′ P-UGACUUAAAGUUCUUUAUGCG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 5: 
               
               
                   
                 5′ P-UUAGCUAAAGACACGAACCGG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 8: 
               
               
                   
                 5′ P-UGACUUAAAGUUCUUUAUGCUC 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 10: 
               
               
                   
                 5′ P-UAUAGCUAAAGACACGAACCC 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 11: 
               
               
                   
                 5′ P-AUAGCUAAAGACACGAACCGG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 12: 
               
               
                   
                 5′ P-UUGAGUGCAUCAUUAUCCAAG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 13: 
               
               
                   
                 5′ P-CUUGACUGCCGCCUCUGCUCG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 14: 
               
               
                   
                 5′ P-GUUGAGUGCAUCAUUAUCCAC 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 15: 
               
               
                   
                 5′ P-UCCUGAUUAUGUACAACACCG 3′. 
               
            
           
         
       
     
     Preferably, the siRNA of the invention presents a guide strand which comprises, or consists of, SEQ ID NO 1. 
     According to a preferred embodiment, the siRNA duplexes of the invention, with guide strand and passenger strand, comprises, or consists of, one of the following duplex sequences: siRNA n° 1 
     
       
         
           
               
               
            
               
                   
                 SEQ ID NO 1: guide strand: 
               
               
                   
                 5′ P-UGAUAGUAGUCAUAAUCGCUA 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 2: passenger strand: 
               
               
                   
                 5′ GCGAUUAUGACUACUAUUUUA 3′. 
               
               
                   
                   
               
               
                   
                 siRNA no 2 
               
               
                   
                 SEQ ID NO 3: guide strand: 
               
               
                   
                 5′ P-UGACUUAAAGUUCUUUAUGCG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 4: passenger strand: 
               
               
                   
                 5′ CAUAAAGAACUUUAAGUCCUC 3′. 
               
               
                   
                   
               
               
                   
                 siRNA no 3 
               
               
                   
                 SEQ ID NO 5: guide strand: 
               
               
                   
                 5′ P-UUAGCUAAAGACACGAACCGG 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 6: passenger strand: 
               
               
                   
                 5′ GGUUCGUGUCUUUAGCUACUC 3′. 
               
               
                   
                   
               
               
                   
                 siRNA no 4 
               
               
                   
                 SEQ ID NO 8: guide strand: 
               
               
                   
                 5′ P-UGACUUAAAGUUCUUUAUGCUC 3′; 
               
               
                   
                   
               
               
                   
                 SEQ ID NO 9: passenger strand: 
               
               
                   
                 5′ GCAUAAAGAACUUUAAGUUUCU 3′. 
               
            
           
         
       
     
     Preferably, the siRNA of the invention comprises, or consists of, the duplex sequences of SEQ ID NO 1 and 2 (siRNA n° 1). 
     The siRNA with guide stands corresponding to SEQ ID 10-15 also comprise passenger strands as to form effective siRNAs duplexes, as described above. 
     Schematic of said siRNA structures are dispatched in  FIG.  1    (|: Watson-Crick base pair, x: mismatch; ′: GU wobble). 
     According to a particular aspect, the invention relates to the siRNAS as identified above. 
     According to another aspect, the invention relates a pharmaceutical composition comprising at least one the siRNAs as defined above, in a pharmaceutically acceptable carrier or excipient. 
     Use of Reverse Micelles to Deliver Unmodified Nucleotides Targeting Virus SARS-Cov-2 Genes 
     The pharmaceutical composition of the present invention describes unmodified oligonucleotides, such as siRNAs, targeting one or more genes of the SARS-CoV-2 Coronavirus virus, formulated in the microemulsion (or reverse micelles) as described herein and intended for the treatment of patients contaminated by this virus. 
     The unmodified oligonucleotides, such as siRNAs, targeting one or more genes of the SARS-CoV-2 are present in the aqueous core of the reverse micelles. 
     The amount of unmodified oligonucleotides, such as siRNAs, targeting one or more genes of SARS-CoV-2 incorporated into the reverse micelle system is determined by their solubility in the hydrophilic phase (aqueous core). Preferably, the amount of unmodified oligonucleotides, such as siRNAs, targeting one or more genes of SARS-CoV-2 included in the reverse micelle system depends on their size. 
     The reverse micelles of the invention allow the oligonucleotide included therein to be administered and transported to cells with a high degree of protection in lipoprotein HDL and vHDL, in particular without affecting its stability. 
     It is known today that a reverse-micelle system can be used for the preparation of nanomaterials, which act as micro reactors. The activity and stability of bio molecules can be controlled, mainly by the concentration of water in this medium. 
     An object of the invention concerns a pharmaceutical composition comprising reverse micelles as defined above and at least a pharmaceutically acceptable carrier, excipient or support, more specifically for use in the treatment of COVID-19. 
     According to a particular embodiment, the pharmaceutical composition is in the form of airless bottle, a capsule, a caplet, an aerosol, a spray, a solution or a soft elastic gelatin capsule. 
     A further object of the invention concerns the use of reverse micelles as defined above for preparing a pharmaceutical composition intended for the treatment of COVID-19. 
     The present invention further concerns a method for the treatment of COVID-19, wherein the method comprises the step of administering into a subject in need of such treatment a therapeutically efficient amount of one or more unmodified oligonucleotides as defined above. 
     More specifically, administration of one or more unmodified oligonucleotides in reverse micelle system as defined herein or pharmaceutical composition comprising the same is a mucosal delivery. 
     As pharmaceutically acceptable excipient, vehicle or carrier, any excipient, vehicle or carrier well-known to the person skilled in the art may be used. Other additives well-known to the person skilled in the art such as stabilisers, drying agents, binders or pH buffers may also be used. Preferred excipients in accordance with the invention promote adherence of the finished product to the mucosa. 
     The compositions of the invention can be administered in different ways, in particular via the oral, nasal, vaginal or rectal route, with a buccal, nasal, vaginal or digestive absorption, or more generally via mucosal tissue absorption. The composition of the invention is preferably administered by buccal route or rectal route, with a buccal mucosa or rectal mucosa absorption, respectively. 
     Within the context of the invention, the term treatment denotes curative, symptomatic, and preventive treatment. As used herein, the term “treatment” of COVID-19 refers to any act intended to extend life span of subjects (or patients) such as therapy and retardation of the disease progression. The treatment can be designed to eradicate the disease, to stop the progression of the disease, and/or to promote the regression of the disease. The term “treatment” of a disease also refers to any act intended to decrease one or more mild symptoms associated with the disease, including fever, cough, shortness of breath, muscle pain, sputum production and/or sore throat. The term “treatment” of the disease also refers to any act intended to decrease one or more severe symptoms associated with the disease, including pneumonia and/or multi-organ failure. More specifically, the treatment according to the invention is intended to delay the appearance of, alleviate, or hinder, the mild symptoms and more particularly the severe symptoms of COVID-19, such as COVID-19 associated pneumonia or multi-organ failure. 
     As used herein, the term “therapeutically effective amount” is intended an amount of unmodified oligonucleotides as defined above, administered to a patient that is sufficient to constitute a treatment of COVID-19 as defined above. In a particular embodiment, the therapeutically effective amount to be administered is an amount sufficient to down regulate or knock down the expression of a target nucleic acid of SARS-CoV-2 virus. The amount of unmodified oligonucleotides as defined above to be administered can be determined by standard procedure well known by those of ordinary skill in the art. Physiological data of the patient (e.g. age, size, and weight), the routes of administration and the disease to be treated have to be taken into account to determine the appropriate dosage. One skilled in the art will recognize that the amount of unmodified oligonucleotides to be administered will be an amount that is sufficient to induce reduction of COVID-19 symptoms or to induce alleviation of one or more symptoms of COVID-19. 
     The subject (or patient) to treat is any mammal, preferably a human being. Preferably, the subject is a human patient, whatever its age or sex. New-borns, infants, children are included as well. More preferably, the patient or subject according to the invention is suspected to be infected by SARS-CoV-2 or has been diagnosed to have CoVID-19 or has been diagnosed as infected by SARS-CoV-2. The standard method of diagnosis is by reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab or throat swab. The infection can also be diagnosed from a combination of symptoms, risk factors and a chest CT scan (Computer Tomography scan) showing features of pneumonia. 
     As used herein, the terms “mucosa” and “mucosal” refer to a mucous tissue such as of the respiratory, digestive, or genital tissue. “Mucosal delivery”, “mucosal administration” and analogous terms as used herein refer to the administration of a composition through a mucosal tissue. “Mucosal delivery”, “mucosal administration” and analogous terms include, but are not limited to, the delivery of a composition through preferably buccal administration, bronchi, gingival, lingual, nasal, buccal, vaginal, rectal, and gastro-intestinal mucosal tissue. Administration according to the invention is more preferably carried out via buccal mucosa or rectal mucosa. 
     EXAMPLES 
     The following examples are intended to exemplify the operation of the present invention but not to limit its scope. 
     Example 1: Manufacture of a Drug for the Treatment of Infectious Pathologies Linked to SARS-CoV-2 Coronavirus—siRNA #1 
     The aim of this study was to evaluate by visual determination the formulation and the stability of the siRNA #1 targeting SARS-CoV-2 in the reverse microemulsion. 
     8.5 g of lecithin were dissolved in 6.8 g of absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 1.4 g of sitosterol were added to the mixture and stirred in the same conditions. 32.6 g of glycerol monooleate was added thereto and magnetic stirring was carried out at 500 r/min for 45 minutes at 37° C. 
     168 mg of a siRNA aqueous solution containing 1.06 mg of siRNA #1 were added to 1148.0 mg of the oil mixture as prepared above and then stirred at room temperature by magnetic stirring at 700 r/min for 30 minutes. 
     The microemulsion was limpid, monophasic and thermodynamically stable. These experiments show that the siRNA #1 is well formulated in the reverse micelle at 800 sg/ml and has no impact on the stability of the system. 
     Other microemulsions with close contents are also prepared and result in similar reverse micelle with a stable system. 
     Example 2: Manufacture of a Drug for the Treatment of Infectious Pathologies Linked to SARS-CoV-2 Coronavirus—siRNA #2, siRNA #3, siRNA #4 
     The aim of this study was to evaluate by visual determination the formulation and the stability of the siRNA #2, #3 et #4 targeting SARS-CoV-2 in the reverse microemulsion. 
     8.5 g of lecithin were dissolved in 6.8 g of absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 1.4 g of sitosterol were added to the mixture and stirred in the same conditions. 32.6 g of glycerol monooleate was added thereto and magnetic stirring was carried out at 500 r/min for 45 minutes at 37° C. 
     168 mg of a siRNA aqueous solution were added to 1148.0 mg of the oil mixture as prepared above and then stirred at room temperature by magnetic stirring at 700 r/min for 30 minutes. The composition of each tested siRNA aqueous solution is in following table 1: 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 tested siRNA aqueous solutions 
               
            
           
           
               
               
               
            
               
                 #2 
                 #3 
                 #4 
               
               
                   
               
               
                 siRNA aqueous  
                 siRNA aqueous  
                 siRNA aqueous  
               
               
                 solution 
                 solution 
                 solution 
               
               
                 containing 1.06 mg  
                 containing 1.06 mg of 
                 containing 1.06 mg  
               
               
                 of siRNA #2 
                 siRNA #3 
                 of siRNA #4 
               
               
                   
               
            
           
         
       
     
     Each microemulsion obtained was limpid, monophasic and thermodynamically stable. These experiments show that the siRNA #2, siRNA #3 and siRNA #4 are well formulated in the reverse micelles at 800 sg/ml and have no impact on the stability of the systems. 
     Example 3: Efficacy Study by Rectal Mucosa Route in SG Hamster Model of SARS-COV-2 
     Objective: 
     Evaluation of 2 reverse micelle systems according to the invention (with siRNA #1 and with siRNA #2) in hamster model of SARS-COV-2 after 4-day treatment. 
     Test Items: 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Name 
                 NanosiRNA ®#1 
                 NanosiRNA ®#2 
                 NanosiRNA ®#SCR 
               
               
                   
               
             
            
               
                 Medesis  Batch 
                 N° 210006 
                 N o : 210007 
                 N o : 210009 
               
               
                 Com- 
                 water in oil 
                 water in oil 
                 water in oil 
               
               
                 position 
                 microemulsion 
                 microemulsion 
                 microemulsion 
               
               
                   
                 containing  
                 containing  
                 containing  
               
               
                   
                 1.0 mg/mL 
                 1.0 mg/mL 
                 1.0 mg/mL 
               
               
                   
                 of siRNA#1,  
                 of siRNA#2, 
                 of scrambled  
               
               
                   
                 targeting 
                 targeting 
                 siRNA. 
               
               
                   
                 the SARS-Cov-2 
                 the SARS-Cov-2 
                   
               
               
                   
                 coronavirus. 
                 coronavirus. 
                   
               
            
           
           
               
               
            
               
                 Description 
                 Homogeneous yellow oily liquid 
               
               
                   
                 Viscosity approx. 80-100 mPa · s at +25° C. and  
               
               
                   
                 approx 40-60 mPa · s at +37° C.. 
               
               
                 Storage  conditions 
                 at room temperature (approximately +15 to +25° C.). 
               
               
                 Expiry date 
                 January 2022 
               
               
                 Quantity 
                 6 mL (3 vials of 2 mL) Clear glass vials  containing 2 mL of drug product 
               
               
                   
               
            
           
         
       
     
     Administration: 
     A constant dosage-volume of 1 mL/kg/day is used for all groups of animals. The quantity of dosage form administered to each animal is adjusted according to the bodyweight. 
     The dosage form is administrated by rectal deposit without anesthesia, using a pipet tip with automatic pipetman. 
     Food and water will be removed before product administration and will be given 30 minutes after administration. 
     Animals: 
     Strain: Golden Syrian hamster model of SARS-COV-2 
     Number: 24 female SG hamsters 
     6-8 weeks old female SG hamsters of 90-120 g are ear-tagged and randomized in the different treatment groups. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                 P 6 virus 
                   
                   
                   
                   
               
               
                   
                   
                 TCID 50   
                   
                   
                 Frequency 
               
               
                 Group 
                 hamsters 
                 inoculum/50 μL 
                 Treatment 
                 Dose 
                 dosing 
                 MOA 
               
               
                   
               
             
            
               
                 Group 1 
                 6 WT 
                 1.89E+06 
                 siRNA 1 
                 1.0 mg/mL 
                 once 
                 Rectal deposit 
               
               
                 Group 2 
                 6 WT 
                 1.89E+06 
                 siRNA 2 
                 1.0 mg/mL 
                 once 
                 Rectal deposit 
               
               
                 Group 3 
                 6 WT 
                 1.89E+06 
                 Scramble 
                 1.0 mg/mL 
                 once 
                 Rectal deposit 
               
               
                   
                 18 hamsters 
               
               
                   
               
            
           
         
       
     
     Duration: 
     The dose formulations will be administrated once daily for a period of 4 days. 
     Collection and Analysing of Samples: 
     Animals are sacrificed: lung and blood collection 
     Lung: 1) Quantification of viral load by real-time quantitative RT-qPCR 
     2) Quantification of infectious viral content by (end-point) titration 
     3) Histological examination for evaluation of inflammation in lung tissues. 
     
       
         
           
               
               
            
               
                 SEQ ID NO 7: 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 attaaaggtt tataccttcc caggtaacaa accaaccaac tttcgatctc ttgtagatct 
                   
               
               
                   
               
               
                 61 
                 gttctctaaa cgaactttaa aatctgtgtg gctgtcactc ggctgcatgc ttagtgcact 
               
               
                   
               
               
                 121 
                 cacgcagtat aattaataac taattactgt cgttgacagg acacgagtaa ctcgtctatc 
               
               
                   
               
               
                 181 
                 ttctgcaggc tgcttacggt ttcgtccgtg ttgcagccga tcatcagcac atctaggttt 
               
               
                   
               
               
                 241 
                 cgtccgggtg tgaccgaaag gtaagatgga gagccttgtc cctggtttca acgagaaaac 
               
               
                   
               
               
                 301 
                 acacgtccaa ctcagtttgc ctgttttaca ggttcgcgac gtgctcgtac gtggctttgg 
               
               
                   
               
               
                 361 
                 agactccgtg gaggaggtct tatcagaggc acgtcaacat cttaaagatg gcacttgtgg 
               
               
                   
               
               
                 421 
                 cttagtagaa gttgaaaaag gcgttttgcc tcaacttgaa cagccctatg tgttcatcaa 
               
               
                   
               
               
                 481 
                 acgttcggat gctcgaactg cacctcatgg tcatgttatg gttgagctgg tagcagaact 
               
               
                   
               
               
                 541 
                 cgaaggcatt cagtacggtc gtagtggtga gacacttggt gtccttgtcc ctcatgtggg 
               
               
                   
               
               
                 601 
                 cgaaatacca gtggcttacc gcaaggttct tcttcgtaag aacggtaata aaggagctgg 
               
               
                   
               
               
                 661 
                 tggccatagt tacggcgccg atctaaagtc atttgactta ggcgacgagc ttggcactga 
               
               
                   
               
               
                 721 
                 tccttatgaa gattttcaag aaaactggaa cactaaacat agcagtggtg ttacccgtga 
               
               
                   
               
               
                 781 
                 actcatgcgt gagcttaacg gaggggcata cactcgctat gtcgataaca acttctgtgg 
               
               
                   
               
               
                 841 
                 ccctgatggc taccctcttg agtgcattaa agaccttcta gcacgtgctg gtaaagcttc 
               
               
                   
               
               
                 901 
                 atgcactttg tccgaacaac tggactttat tgacactaag aggggtgtat actgctgccg 
               
               
                   
               
               
                 961 
                 tgaacatgag catgaaattg cttggtacac ggaacgttct gaaaagagct atgaattgca 
               
               
                   
               
               
                 1021 
                 gacacctttt gaaattaaat tggcaaagaa atttgacacc ttcaatgggg aatgtccaaa 
               
               
                   
               
               
                 1081 
                 ttttgtattt cccttaaatt ccataatcaa gactattcaa ccaagggttg aaaagaaaaa 
               
               
                   
               
               
                 1141 
                 gcttgatggc tttatgggta gaattcgatc tgtctatcca gttgcgtcac caaatgaatg 
               
               
                   
               
               
                 1201 
                 caaccaaatg tgcctttcaa ctctcatgaa gtgtgatcat tgtggtgaaa cttcatggca 
               
               
                   
               
               
                 1261 
                 gacgggcgat tttgttaaag ccacttgcga attttgtggc actgagaatt tgactaaaga 
               
               
                   
               
               
                 1321 
                 aggtgccact acttgtggtt acttacccca aaatgctgtt gttaaaattt attgtccagc 
               
               
                   
               
               
                 1381 
                 atgtcacaat tcagaagtag gacctgagca tagtcttgcc gaataccata atgaatctgg 
               
               
                   
               
               
                 1441 
                 cttgaaaacc attcttcgta agggtggtcg cactattgcc tttggaggct gtgtgttctc 
               
               
                   
               
               
                 1501 
                 ttatgttggt tgccataaca agtgtgccta ttgggttcca cgtgctagcg ctaacatagg 
               
               
                   
               
               
                 1561 
                 ttgtaaccat acaggtgttg ttggagaagg ttccgaaggt cttaatgaca accttcttga 
               
               
                   
               
               
                 1621 
                 aatactccaa aaagagaaag tcaacatcaa tattgttggt gactttaaac ttaatgaaga 
               
               
                   
               
               
                 1681 
                 gatcgccatt attttggcat ctttttctgc ttccacaagt gcttttgtgg aaactgtgaa 
               
               
                   
               
               
                 1741 
                 aggtttggat tataaagcat tcaaacaaat tgttgaatcc tgtggtaatt ttaaagttac 
               
               
                   
               
               
                 1801 
                 aaaaggaaaa gctaaaaaag gtgcctggaa tattggtgaa cagaaatcaa tactgagtcc 
               
               
                   
               
               
                 1861 
                 tctttatgca tttgcatcag aggctgctcg tgttgtacga tcaattttct cccgcactct 
               
               
                   
               
               
                 1921 
                 tgaaactgct caaaattctg tgcgtgtttt acagaaggcc gctataacaa tactagatgg 
               
               
                   
               
               
                 1981 
                 aatttcacag tattcactga gactcattga tgctatgatg ttcacatctg atttggctac 
               
               
                   
               
               
                 2041 
                 taacaatcta gttgtaatgg cctacattac aggtggtgtt gttcagttga cttcgcagtg 
               
               
                   
               
               
                 2101 
                 gctaactaac atctttggca ctgtttatga aaaactcaaa cccgtccttg attggcttga 
               
               
                   
               
               
                 2161 
                 agagaagttt aaggaaggtg tagagtttct tagagacggt tgggaaattg ttaaatttat 
               
               
                   
               
               
                 2221 
                 ctcaacctgt gcttgtgaaa ttgtcggtgg acaaattgtc acctgtgcaa aggaaattaa 
               
               
                   
               
               
                 2281 
                 ggagagtgtt cagacattct ttaagcttgt aaataaattt ttggctttgt gtgctgactc 
               
               
                   
               
               
                 2341 
                 tatcattatt ggtggagcta aacttaaagc cttgaattta ggtgaaacat ttgtcacgca 
               
               
                   
               
               
                 2401 
                 ctcaaaggga ttgtacagaa agtgtgttaa atccagagaa gaaactggcc tactcatgcc 
               
               
                   
               
               
                 2461 
                 tctaaaagcc ccaaaagaaa ttatcttctt agagggagaa acacttccca cagaagtgtt 
               
               
                   
               
               
                 2521 
                 aacagaggaa gttgtcttga aaactggtga tttacaacca ttagaacaac ctactagtga 
               
               
                   
               
               
                 2581 
                 agctgttgaa gctccattgg ttggtacacc agtttgtatt aacgggctta tgttgctcga 
               
               
                   
               
               
                 2641 
                 aatcaaagac acagaaaagt actgtgccct tgcacctaat atgatggtaa caaacaatac 
               
               
                   
               
               
                 2701 
                 cttcacactc aaaggcggtg caccaacaaa ggttactttt ggtgatgaca ctgtgataga 
               
               
                   
               
               
                 2761 
                 agtgcaaggt tacaagagtg tgaatatcac ttttgaactt gatgaaagga ttgataaagt 
               
               
                   
               
               
                 2821 
                 acttaatgag aagtgctctg cctatacagt tgaactcggt acagaagtaa atgagttcgc 
               
               
                   
               
               
                 2881 
                 ctgtgttgtg gcagatgctg tcataaaaac tttgcaacca gtatctgaat tacttacacc 
               
               
                   
               
               
                 2941 
                 actgggcatt gatttagatg agtggagtat ggctacatac tacttatttg atgagtctgg 
               
               
                   
               
               
                 3001 
                 tgagtttaaa ttggcttcac atatgtattg ttctttctac cctccagatg aggatgaaga 
               
               
                   
               
               
                 3061 
                 agaaggtgat tgtgaagaag aagagtttga gccatcaact caatatgagt atggtactga 
               
               
                   
               
               
                 3121 
                 agatgattac caaggtaaac ctttggaatt tggtgccact tctgctgctc ttcaacctga 
               
               
                   
               
               
                 3181 
                 agaagagcaa gaagaagatt ggttagatga tgatagtcaa caaactgttg gtcaacaaga 
               
               
                   
               
               
                 3241 
                 cggcagtgag gacaatcaga caactactat tcaaacaatt gttgaggttc aacctcaatt 
               
               
                   
               
               
                 3301 
                 agagatggaa cttacaccag ttgttcagac tattgaagtg aatagtttta gtggttattt 
               
               
                   
               
               
                 3361 
                 aaaacttact gacaatgtat acattaaaaa tgcagacatt gtggaagaag ctaaaaaggt 
               
               
                   
               
               
                 3421 
                 aaaaccaaca gtggttgtta atgcagccaa tgtttacctt aaacatggag gaggtgttgc 
               
               
                   
               
               
                 3481 
                 aggagcctta aataaggcta ctaacaatgc catgcaagtt gaatetgatg attacatagc 
               
               
                   
               
               
                 3541 
                 tactaatgga ccacttaaag tgggtggtag ttgtgtttta agcggacaca atcttgctaa 
               
               
                   
               
               
                 3601 
                 acactgtctt catgttgtcg gcccaaatgt taacaaaggt gaagacattc aacttcttaa 
               
               
                   
               
               
                 3661 
                 gagtgcttat gaaaatttta atcagcacga agttctactt gcaccattat tatcagctgg 
               
               
                   
               
               
                 3721 
                 tatttttggt gctgacccta tacattcttt aagagtttgt gtagatactg ttcgcacaaa 
               
               
                   
               
               
                 3781 
                 tgtctactta gctgtctttg ataaaaatct ctatgacaaa cttgtttcaa gctttttgga 
               
               
                   
               
               
                 3841 
                 aatgaagagt gaaaagcaag ttgaacaaaa gatcgctgag attcctaaag aggaagttaa 
               
               
                   
               
               
                 3901 
                 gccatttata actgaaagta aaccttcagt tgaacagaga aaacaagatg ataagaaaat 
               
               
                   
               
               
                 3961 
                 caaagcttgt gttgaagaag ttacaacaac tctggaagaa actaagttcc tcacagaaaa 
               
               
                   
               
               
                 4021 
                 cttgttactt tatattgaca ttaatggcaa tcttcatcca gattctgcca ctcttgttag 
               
               
                   
               
               
                 4081 
                 tgacattgac atcactttct taaagaaaga tgctccatat atagtgggtg atgttgttca 
               
               
                   
               
               
                 4141 
                 agagggtgtt ttaactgctg tggttatacc tactaaaaag gctggtggca ctactgaaat 
               
               
                   
               
               
                 4201 
                 gctagcgaaa gctttgagaa aagtgccaac agacaattat ataaccactt acccgggtca 
               
               
                   
               
               
                 4261 
                 gggtttaaat ggttacactg tagaggaggc aaagacagtg cttaaaaagt gtaaaagtgc 
               
               
                   
               
               
                 4321 
                 cttttacatt ctaccatcta ttatctctaa tgagaagcaa gaaattcttg gaactgtttc 
               
               
                   
               
               
                 4381 
                 ttggaatttg cgagaaatgc ttgcacatgc agaagaaaca cgcaaattaa tgcctgtctg 
               
               
                   
               
               
                 4441 
                 tgtggaaact aaagccatag tttcaactat acagcgtaaa tataagggta ttaaaataca 
               
               
                   
               
               
                 4501 
                 agagggtgtg gttgattatg gtgctagatt ttacttttac accagtaaaa caactgtagc 
               
               
                   
               
               
                 4561 
                 gtcacttatc aacacactta acgatctaaa tgaaactctt gttacaatgc cacttggcta 
               
               
                   
               
               
                 4621 
                 tgtaacacat ggcttaaatt tggaagaagc tgctcggtat atgagatctc tcaaagtgcc 
               
               
                   
               
               
                 4681 
                 agctacagtt tctgtttctt cacctgatgc tgttacagcg tataatggtt atcttacttc 
               
               
                   
               
               
                 4741 
                 ttcttctaaa acacctgaag aacattttat tgaaaccatc tcacttgctg gttcctataa 
               
               
                   
               
               
                 4801 
                 agattggtcc tattctggac aatctacaca actaggtata gaatttctta agagaggtga 
               
               
                   
               
               
                 4861 
                 taaaagtgta tattacacta gtaatcctac cacattccac ctagatggtg aagttatcac 
               
               
                   
               
               
                 4921 
                 ctttgacaat cttaagacac ttctttcttt gagagaagtg aggactatta aggtgtttac 
               
               
                   
               
               
                 4981 
                 aacagtagac aacattaacc tccacacgca agttgtggac atgtcaatga catatggaca 
               
               
                   
               
               
                 5041 
                 acagtttggt ccaacttatt tggatggagc tgatgttact aaaataaaac ctcataattc 
               
               
                   
               
               
                 5101 
                 acatgaaggt aaaacatttt atgttttacc taatgatgac actctacgtg ttgaggcttt 
               
               
                   
               
               
                 5161 
                 tgagtactac cacacaactg atcctagttt tctgggtagg tacatgtcag cattaaatca 
               
               
                   
               
               
                 5221 
                 cactaaaaag tggaaatacc cacaagttaa tggtttaact tctattaaat gggcagataa 
               
               
                   
               
               
                 5281 
                 caactgttat cttgccactg cattgttaac actccaacaa atagagttga agtttaatcc 
               
               
                   
               
               
                 5341 
                 acctgctcta caagatgctt attacagagc aagggctggt gaagctgcta acttttgtgc 
               
               
                   
               
               
                 5401 
                 acttatctta gcctactgta ataagacagt aggtgagtta ggtgatgtta gagaaacaat 
               
               
                   
               
               
                 5461 
                 gagttacttg tttcaacatg ccaatttaga ttcttgcaaa agagtcttga acgtggtgtg 
               
               
                   
               
               
                 5521 
                 taaaacttgt ggacaacagc agacaaccct taagggtgta gaagctgtta tgtacatggg 
               
               
                   
               
               
                 5581 
                 cacactttct tatgaacaat ttaagaaagg tgttcagata ccttgtacgt gtggtaaaca 
               
               
                   
               
               
                 5641 
                 agctacaaaa tatctagtac aacaggagtc accttttgtt atgatgtcag caccacctgc 
               
               
                   
               
               
                 5701 
                 tcagtatgaa cttaagcatg gtacatttac ttgtgctagt gagtacactg gtaattacca 
               
               
                   
               
               
                 5761 
                 gtgtggtcac tataaacata taacttctaa agaaactttg tattgcatag acggtgcttt 
               
               
                   
               
               
                 5821 
                 acttacaaag tcctcagaat acaaaggtcc tattacggat gttttctaca aagaaaacag 
               
               
                   
               
               
                 5881 
                 ttacacaaca accataaaac cagttactta taaattggat ggtgttgttt gtacagaaat 
               
               
                   
               
               
                 5941 
                 tgaccctaag ttggacaatt attataagaa agacaattct tatttcacag agcaaccaat 
               
               
                   
               
               
                 6001 
                 tgatcttgta ccaaaccaac catatccaaa cgcaagcttc gataatttta agtttgtatg 
               
               
                   
               
               
                 6061 
                 tgataatatc aaatttgctg atgatttaaa ccagttaact ggttataaga aacctgcttc 
               
               
                   
               
               
                 6121 
                 aagagagctt aaagttacat ttttccctga cttaaatggt gatgtggtgg ctattgatta 
               
               
                   
               
               
                 6181 
                 taaacactac acaccctctt ttaagaaagg agctaaattg ttacataaac ctattgtttg 
               
               
                   
               
               
                 6241 
                 gcatgttaac aatgcaacta ataaagccac gtataaacca aatacctggt gtatacgttg 
               
               
                   
               
               
                 6301 
                 tctttggagc acaaaaccag ttgaaacatc aaattcgttt gatgtactga agtcagagga 
               
               
                   
               
               
                 6361 
                 cgcgcaggga atggataatc ttgcctgcga agatctaaaa ccagtctctg aagaagtagt 
               
               
                   
               
               
                 6421 
                 ggaaaatcct accatacaga aagacgttct tgagtgtaat gtgaaaacta ccgaagttgt 
               
               
                   
               
               
                 6481 
                 aggagacatt atacttaaac cagcaaataa tagtttaaaa attacagaag aggttggcca 
               
               
                   
               
               
                 6541 
                 cacagatcta atggctgctt atgtagacaa ttctagtctt actattaaga aacctaatga 
               
               
                   
               
               
                 6601 
                 attatctaga gtattaggtt tgaaaaccct tgctactcat ggtttagctg ctgttaatag 
               
               
                   
               
               
                 6661 
                 tgtcccttgg gatactatag ctaattatgc taagcctttt cttaacaaag ttgttagtac 
               
               
                   
               
               
                 6721 
                 aactactaac atagttacac ggtgtttaaa ccgtgtttgt actaattata tgccttattt 
               
               
                   
               
               
                 6781 
                 ctttacttta ttgctacaat tgtgtacttt tactagaagt acaaattcta gaattaaagc 
               
               
                   
               
               
                 6841 
                 atctatgccg actactatag caaagaatac tgttaagagt gtcggtaaat tttgtctaga 
               
               
                   
               
               
                 6901 
                 ggcttcattt aattatttga agtcacctaa tttttctaaa ctgataaata ttataatttg 
               
               
                   
               
               
                 6961 
                 gtttttacta ttaagtgttt gcctaggttc tttaatctac tcaaccgctg ctttaggtgt 
               
               
                   
               
               
                 7021 
                 tttaatgtct aatttaggca tgccttctta ctgtactggt tacagagaag gctatttgaa 
               
               
                   
               
               
                 7081 
                 ctctactaat gtcactattg caacctactg tactggttct ataccttgta gtgtttgtct 
               
               
                   
               
               
                 7141 
                 tagtggttta gattctttag acacctatcc ttctttagaa actatacaaa ttaccatttc 
               
               
                   
               
               
                 7201 
                 atcttttaaa tgggatttaa ctgcttttgg cttagttgca gagtggtttt tggcatatat 
               
               
                   
               
               
                 7261 
                 tcttttcact aggtttttct atgtacttgg attggctgca atcatgcaat tgtttttcag 
               
               
                   
               
               
                 7321 
                 ctattttgca gtacatttta ttagtaattc ttggcttatg tggttaataa ttaatcttgt 
               
               
                   
               
               
                 7381 
                 acaaatggcc ccgatttcag ctatggttag aatgtacatc ttctttgcat cattttatta 
               
               
                   
               
               
                 7441 
                 tgtatggaaa agttatgtgc atgttgtaga cggttgtaat tcatcaactt gtatgatgtg 
               
               
                   
               
               
                 7501 
                 ttacaaacgt aatagagcaa caagagtcga atgtacaact attgttaatg gtgttagaag 
               
               
                   
               
               
                 7561 
                 gtccttttat gtctatgcta atggaggtaa aggcttttgc aaactacaca attggaattg 
               
               
                   
               
               
                 7621 
                 tgttaattgt gatacattct gtgctggtag tacatttatt agtgatgaag ttgcgagaga 
               
               
                   
               
               
                 7681 
                 cttgtcacta cagtttaaaa gaccaataaa tcctactgac cagtcttctt acatcgttga 
               
               
                   
               
               
                 7741 
                 tagtgttaca gtgaagaatg gttccatcca tctttacttt gataaagctg gtcaaaagac 
               
               
                   
               
               
                 7801 
                 ttatgaaaga cattctctct ctcattttgt taacttagac aacctgagag ctaataacac 
               
               
                   
               
               
                 7861 
                 taaaggttca ttgcctatta atgttatagt ttttgatggt aaatcaaaat gtgaagaatc 
               
               
                   
               
               
                 7921 
                 atctgcaaaa tcagcgtctg tttactacag tcagcttatg tgtcaaccta tactgttact 
               
               
                   
               
               
                 7981 
                 agatcaggca ttagtgtctg atgttggtga tagtgcggaa gttgcagtta aaatgtttga 
               
               
                   
               
               
                 8041 
                 tgcttacgtt aatacgtttt catcaacttt taacgtacca atggaaaaac tcaaaacact 
               
               
                   
               
               
                 8101 
                 agttgcaact gcagaagctg aacttgcaaa gaatgtgtcc ttagacaatg tcttatctac 
               
               
                   
               
               
                 8161 
                 ttttatttca gcagctcggc aagggtttgt tgattcagat gtagaaacta aagatgttgt 
               
               
                   
               
               
                 8221 
                 tgaatgtctt aaattgtcac atcaatctga catagaagtt actggcgata gttgtaataa 
               
               
                   
               
               
                 8281 
                 ctatatgctc acctataaca aagttgaaaa catgacaccc cgtgaccttg gtgcttgtat 
               
               
                   
               
               
                 8341 
                 tgactgtagt gcgcgtcata ttaatgcgca ggtagcaaaa agtcacaaca ttgctttgat 
               
               
                   
               
               
                 8401 
                 atggaacgtt aaagatttca tgtcattgtc tgaacaacta cgaaaacaaa tacgtagtgc 
               
               
                   
               
               
                 8461 
                 tgctaaaaag aataacttac cttttaagtt gacatgtgca actactagac aagttgttaa 
               
               
                   
               
               
                 8521 
                 tgttgtaaca acaaagatag cacttaaggg tggtaaaatt gttaataatt ggttgaagca 
               
               
                   
               
               
                 8581 
                 gttaattaaa gttacacttg tgttcctttt tgttgctgct attttctatt taataacacc 
               
               
                   
               
               
                 8641 
                 tgttcatgtc atgtctaaac atactgactt ttcaagtgaa atcataggat acaaggctat 
               
               
                   
               
               
                 8701 
                 tgatggtggt gtcactcgtg acatagcatc tacagatact tgttttgcta acaaacatgc 
               
               
                   
               
               
                 8761 
                 tgattttgac acatggttta gccagcgtgg tggtagttat actaatgaca aagcttgccc 
               
               
                   
               
               
                 8821 
                 attgattgct gcagtcataa caagagaagt gggttttgtc gtgcctggtt tgcctggcac 
               
               
                   
               
               
                 8881 
                 gatattacgc acaactaatg gtgacttttt gcatttctta cctagagttt ttagtgcagt 
               
               
                   
               
               
                 8941 
                 tggtaacatc tgttacacac catcaaaact tatagagtac actgactttg caacatcagc 
               
               
                   
               
               
                 9001 
                 ttgtgttttg gctgctgaat gtacaatttt taaagatgct tctggtaagc cagtaccata 
               
               
                   
               
               
                 9061 
                 ttgttatgat accaatgtac tagaaggttc tgttgcttat gaaagtttac gccctgacac 
               
               
                   
               
               
                 9121 
                 acgttatgtg ctcatggatg gctctattat tcaatttcct aacacctacc ttgaaggttc 
               
               
                   
               
               
                 9181 
                 tgttagagtg gtaacaactt ttgattctga gtactgtagg cacggcactt gtgaaagatc 
               
               
                   
               
               
                 9241 
                 agaagctggt gtttgtgtat ctactagtgg tagatgggta cttaacaatg attattacag 
               
               
                   
               
               
                 9301 
                 atctttacca ggagttttct gtggtgtaga tgctgtaaat ttacttacta atatgtttac 
               
               
                   
               
               
                 9361 
                 accactaatt caacctattg gtgctttgga catatcagca tctatagtag ctggtggtat 
               
               
                   
               
               
                 9421 
                 tgtagctatc gtagtaacat gccttgccta ctattttatg aggtttagaa gagcttttgg 
               
               
                   
               
               
                 9481 
                 tgaatacagt catgtagttg cctttaatac tttactattc cttatgtcat tcactgtact 
               
               
                   
               
               
                 9541 
                 ctgtttaaca ccagtttact cattcttacc tggtgtttat tctgttattt acttgtactt 
               
               
                   
               
               
                 9601 
                 gacattttat cttactaatg atgtttcttt tttagcacat attcagtgga tggttatgtt 
               
               
                   
               
               
                 9661 
                 cacaccttta gtacctttct ggataacaat tgcttatatc atttgtattt ccacaaagca 
               
               
                   
               
               
                 9721 
                 tttctattgg ttctttagta attacctaaa gagacgtgta gtctttaatg gtgtttcctt 
               
               
                   
               
               
                 9781 
                 tagtactttt gaagaagctg cgctgtgcac ctttttgtta aataaagaaa tgtatctaaa 
               
               
                   
               
               
                 9841 
                 gttgcgtagt gatgtgctat tacctcttac gcaatataat agatacttag ctctttataa 
               
               
                   
               
               
                 9901 
                 taagtacaag tattttagtg gagcaatgga tacaactagc tacagagaag ctgcttgttg 
               
               
                   
               
               
                 9961 
                 tcatctcgca aaggctctca atgacttcag taactcaggt tctgatgttc tttaccaacc 
               
               
                   
               
               
                 10021 
                 accacaaacc tctatcacct cagctgtttt gcagagtggt tttagaaaaa tggcattccc 
               
               
                   
               
               
                 10081 
                 atctggtaaa gttgagggtt gtatggtaca agtaacttgt ggtacaacta cacttaacgg 
               
               
                   
               
               
                 10141 
                 tctttggctt gatgacgtag tttactgtcc aagacatgtg atctgcacct ctgaagacat 
               
               
                   
               
               
                 10201 
                 gcttaaccct aattatgaag atttactcat tcgtaagtct aatcataatt tcttggtaca 
               
               
                   
               
               
                 10261 
                 ggctggtaat gttcaactca gggttattgg acattctatg caaaattgtg tacttaagct 
               
               
                   
               
               
                 10321 
                 taaggttgat acagccaatc ctaagacacc taagtataag tttgttcgca ttcaaccagg 
               
               
                   
               
               
                 10381 
                 acagactttt tcagtgttag cttgttacaa tggttcacca tctggtgttt accaatgtgc 
               
               
                   
               
               
                 10441 
                 tatgaggccc aatttcacta ttaagggttc attccttaat ggttcatgtg gtagtgttgg 
               
               
                   
               
               
                 10501 
                 ttttaacata gattatgact gtgtctcttt ttgttacatg caccatatgg aattaccaac 
               
               
                   
               
               
                 10561 
                 tggagttcat gctggcacag acttagaagg taacttttat ggaccttttg ttgacaggca 
               
               
                   
               
               
                 10621 
                 aacagcacaa gcagctggta cggacacaac tattacagtt aatgttttag cttggttgta 
               
               
                   
               
               
                 10681 
                 cgctgctgtt ataaatggag acaggtggtt tctcaatcga tttaccacaa ctcttaatga 
               
               
                   
               
               
                 10741 
                 ctttaacctt gtggctatga agtacaatta tgaacctcta acacaagacc atgttgacat 
               
               
                   
               
               
                 10801 
                 actaggacct ctttctgctc aaactggaat tgccgtttta gatatgtgtg cttcattaaa 
               
               
                   
               
               
                 10861 
                 agaattactg caaaatggta tgaatggacg taccatattg ggtagtgctt tattagaaga 
               
               
                   
               
               
                 10921 
                 tgaatttaca ccttttgatg ttgttagaca atgctcaggt gttactttcc aaagtgcagt 
               
               
                   
               
               
                 10981 
                 gaaaagaaca atcaagggta cacaccactg gttgttactc acaattttga cttcactttt 
               
               
                   
               
               
                 11041 
                 agttttagtc cagagtactc aatggtcttt gttctttttt ttgtatgaaa atgccttttt 
               
               
                   
               
               
                 11101 
                 accttttgct atgggtatta ttgctatgtc tgcttttgca atgatgtttg tcaaacataa 
               
               
                   
               
               
                 11161 
                 gcatgcattt ctctgtttgt ttttgttacc ttctcttgcc actgtagctt attttaatat 
               
               
                   
               
               
                 11221 
                 ggtctatatg cctgctagtt gggtgatgcg tattatgaca tggttggata tggttgatac 
               
               
                   
               
               
                 11281 
                 tagtttgtct ggttttaagc taaaagactg tgttatgtat gcatcagctg tagtgttact 
               
               
                   
               
               
                 11341 
                 aatccttatg acagcaagaa ctgtgtatga tgatggtgct aggagagtgt ggacacttat 
               
               
                   
               
               
                 11401 
                 gaatgtcttg acactcgttt ataaagttta ttatggtaat gctttagatc aagccatttc 
               
               
                   
               
               
                 11461 
                 catgtgggct cttataatct ctgttacttc taactactca ggtgtagtta caactgtcat 
               
               
                   
               
               
                 11521 
                 gtttttggcc agaggtattg tttttatgtg tgttgagtat tgccctattt tcttcataac 
               
               
                   
               
               
                 11581 
                 tggtaataca cttcagtgta taatgctagt ttattgtttc ttaggctatt tttgtacttg 
               
               
                   
               
               
                 11641 
                 ttactttggc ctcttttgtt tactcaaccg ctactttaga ctgactcttg gtgtttatga 
               
               
                   
               
               
                 11701 
                 ttacttagtt tctacacagg agtttagata tatgaattca cagggactac tcccacccaa 
               
               
                   
               
               
                 11761 
                 gaatagcata gatgccttca aactcaacat taaattgttg ggtgttggtg gcaaaccttg 
               
               
                   
               
               
                 11821 
                 tatcaaagta gccactgtac agtctaaaat gtcagatgta aagtgcacat cagtagtctt 
               
               
                   
               
               
                 11881 
                 actctcagtt ttgcaacaac tcagagtaga atcatcatct aaattgtggg ctcaatgtgt 
               
               
                   
               
               
                 11941 
                 ccagttacac aatgacattc tcttagctaa agatactact gaagcctttg aaaaaatggt 
               
               
                   
               
               
                 12001 
                 ttcactactt tctgttttgc tttccatgca gggtgctgta gacataaaca agctttgtga 
               
               
                   
               
               
                 12061 
                 agaaatgctg gacaacaggg caaccttaca agctatagcc tcagagttta gttcccttcc 
               
               
                   
               
               
                 12121 
                 atcatatgca gcttttgcta ctgctcaaga agcttatgag caggctgttg ctaatggtga 
               
               
                   
               
               
                 12181 
                 ttctgaagtt gttcttaaaa agttgaagaa gtctttgaat gtggctaaat ctgaatttga 
               
               
                   
               
               
                 12241 
                 ccgtgatgca gccatgcaac gtaagttgga aaagatggct gatcaagcta tgacccaaat 
               
               
                   
               
               
                 12301 
                 gtataaacag gctagatctg aggacaagag ggcaaaagtt actagtgcta tgcagacaat 
               
               
                   
               
               
                 12361 
                 gcttttcact atgcttagaa agttggataa tgatgcactc aacaacatta tcaacaatgc 
               
               
                   
               
               
                 12421 
                 aagagatggt tgtgttccct tgaacataat acctcttaca acagcagcca aactaatggt 
               
               
                   
               
               
                 12481 
                 tgtcatacca gactataaca catataaaaa tacgtgtgat ggtacaacat ttacttatgc 
               
               
                   
               
               
                 12541 
                 atcagcattg tgggaaatcc aacaggttgt agatgcagat agtaaaattg ttcaacttag 
               
               
                   
               
               
                 12601 
                 tgaaattagt atggacaatt cacctaattt agcatggcct cttattgtaa cagctttaag 
               
               
                   
               
               
                 12661 
                 ggccaattct gctgtcaaat tacagaataa tgagcttagt cctgttgcac tacgacagat 
               
               
                   
               
               
                 12721 
                 gtcttgtgct gccggtacta cacaaactgc ttgcactgat gacaatgcgt tagcttacta 
               
               
                   
               
               
                 12781 
                 caacacaaca aagggaggta ggtttgtact tgcactgtta tccgatttac aggatttgaa 
               
               
                   
               
               
                 12841 
                 atgggctaga ttccctaaga gtgatggaac tggtactatc tatacagaac tggaaccacc 
               
               
                   
               
               
                 12901 
                 ttgtaggttt gttacagaca cacctaaagg tcctaaagtg aagtatttat actttattaa 
               
               
                   
               
               
                 12961 
                 aggattaaac aacctaaata gaggtatggt acttggtagt ttagctgcca cagtacgtct 
               
               
                   
               
               
                 13021 
                 acaagctggt aatgcaacag aagtgcctgc caattcaact gtattatctt tctgtgcttt 
               
               
                   
               
               
                 13081 
                 tgctgtagat gctgctaaag cttacaaaga ttatctagct agtgggggac aaccaatcac 
               
               
                   
               
               
                 13141 
                 taattgtgtt aagatgttgt gtacacacac tggtactggt caggcaataa cagttacacc 
               
               
                   
               
               
                 13201 
                 ggaagccaat atggatcaag aatcctttgg tggtgcatcg tgttgtctgt actgccgttg 
               
               
                   
               
               
                 13261 
                 ccacatagat catccaaatc ctaaaggatt ttgtgactta aaaggtaagt atgtacaaat 
               
               
                   
               
               
                 13321 
                 acctacaact tgtgctaatg accctgtggg ttttacactt aaaaacacag tctgtaccgt 
               
               
                   
               
               
                 13381 
                 ctgcggtatg tggaaaggtt atggctgtag ttgtgatcaa ctccgcgaac ccatgcttca 
               
               
                   
               
               
                 13441 
                 gtcagctgat gcacaatcgt ttttaaacgg gtttgcggtg taagtgcagc ccgtcttaca 
               
               
                   
               
               
                 13501 
                 ccgtgcggca caggcactag tactgatgtc gtatacaggg cttttgacat ctacaatgat 
               
               
                   
               
               
                 13561 
                 aaagtagctg gttttgctaa attcctaaaa actaattgtt gtcgcttcca agaaaaggac 
               
               
                   
               
               
                 13621 
                 gaagatgaca atttaattga ttcttacttt gtagttaaga gacacacttt ctctaactac 
               
               
                   
               
               
                 13681 
                 caacatgaag aaacaattta taatttactt aaggattgtc cagctgttgc taaacatgac 
               
               
                   
               
               
                 13741 
                 ttctttaagt ttagaataga cggtgacatg gtaccacata tatcacgtca acgtcttact 
               
               
                   
               
               
                 13801 
                 aaatacacaa tggcagacct cgtctatgct ttaaggcatt ttgatgaagg taattgtgac 
               
               
                   
               
               
                 13861 
                 acattaaaag aaatacttgt cacatacaat tgttgtgatg atgattattt caataaaaag 
               
               
                   
               
               
                 13921 
                 gactggtatg attttgtaga aaacccagat atattacgcg tatacgccaa ettaggtgaa 
               
               
                   
               
               
                 13981 
                 cgtgtacgcc aagctttgtt aaaaacagta caattctgtg atgccatgcg aaatgctggt 
               
               
                   
               
               
                 14041 
                 attgttggtg tactgacatt agataatcaa gatctcaatg gtaactggta tgatttcggt 
               
               
                   
               
               
                 14101 
                 gatttcatac aaaccacgcc aggtagtgga gttcctgttg tagattctta ttattcattg 
               
               
                   
               
               
                 14161 
                 ttaatgccta tattaacctt gaccagggct ttaactgcag agtcacatgt tgacactgac 
               
               
                   
               
               
                 14221 
                 ttaacaaagc cttacattaa gtgggatttg ttaaaatatg acttcacgga agagaggtta 
               
               
                   
               
               
                 14281 
                 aaactctttg accgttattt taaatattgg gatcagacat accacccaaa ttgtgttaac 
               
               
                   
               
               
                 14341 
                 tgtttggatg acagatgcat tctgcattgt gcaaacttta atgttttatt ctctacagtg 
               
               
                   
               
               
                 14401 
                 ttcccaccta caagttttgg accactagtg agaaaaatat ttgttgatgg tgttccattt 
               
               
                   
               
               
                 14461 
                 gtagtttcaa ctggatacca cttcagagag ctaggtgttg tacataatca ggatgtaaac 
               
               
                   
               
               
                 14521 
                 ttacatagct ctagacttag ttttaaggaa ttacttgtgt atgctgctga ccctgctatg 
               
               
                   
               
               
                 14581 
                 cacgctgctt ctggtaatct attactagat aaacgcacta cgtgcttttc agtagctgca 
               
               
                   
               
               
                 14641 
                 cttactaaca atgttgcttt tcaaactgtc aaacccggta attttaacaa agacttctat 
               
               
                   
               
               
                 14701 
                 gactttgctg tgtctaaggg tttctttaag gaaggaagtt ctgttgaatt aaaacacttc 
               
               
                   
               
               
                 14761 
                 ttctttgctc aggatggtaa tgctgctatc agcgattatg actactatcg ttataatcta 
               
               
                   
               
               
                 14821 
                 ccaacaatgt gtgatatcag acaactacta tttgtagttg aagttgttga taagtacttt 
               
               
                   
               
               
                 14881 
                 gattgttacg atggtggctg tattaatgct aaccaagtca tcgtcaacaa cctagacaaa 
               
               
                   
               
               
                 14941 
                 tcagctggtt ttccatttaa taaatggggt aaggctagac tttattatga ttcaatgagt 
               
               
                   
               
               
                 15001 
                 tatgaggatc aagatgcact tttcgcatat acaaaacgta atgtcatccc tactataact 
               
               
                   
               
               
                 15061 
                 caaatgaatc ttaagtatgc cattagtgca aagaatagag ctcgcaccgt agctggtgtc 
               
               
                   
               
               
                 15121 
                 tctatctgta gtactatgac caatagacag tttcatcaaa aattattgaa atcaatagcc 
               
               
                   
               
               
                 15181 
                 gccactagag gagctactgt agtaattgga acaagcaaat tctatggtgg ttggcacaac 
               
               
                   
               
               
                 15241 
                 atgttaaaaa ctgtttatag tgatgtagaa aaccctcacc ttatgggttg ggattatcct 
               
               
                   
               
               
                 15301 
                 aaatgtgata gagccatgcc taacatgctt agaattatgg cctcacttgt tcttgctcgc 
               
               
                   
               
               
                 15361 
                 aaacatacaa cgtgttgtag cttgtcacac cgtttctata gattagctaa tgagtgtgct 
               
               
                   
               
               
                 15421 
                 caagtattga gtgaaatggt catgtgtggc ggttcactat atgttaaacc aggtggaacc 
               
               
                   
               
               
                 15481 
                 tcatcaggag atgccacaac tgcttatgct aatagtgttt ttaacatttg tcaagctgtc 
               
               
                   
               
               
                 15541 
                 acggccaatg ttaatgcact tttatctact gatggtaaca aaattgccga taagtatgtc 
               
               
                   
               
               
                 15601 
                 cgcaatttac aacacagact ttatgagtgt ctctatagaa atagagatgt tgacacagac 
               
               
                   
               
               
                 15661 
                 tttgtgaatg agttttacgc atatttgcgt aaacatttct caatgatgat actctctgac 
               
               
                   
               
               
                 15721 
                 gatgctgttg tgtgtttcaa tagcacttat gcatctcaag gtctagtggc tagcataaag 
               
               
                   
               
               
                 15781 
                 aactttaagt cagttcttta ttatcaaaac aatgttttta tgtctgaagc aaaatgttgg 
               
               
                   
               
               
                 15841 
                 actgagactg accttactaa aggacctcat gaattttgct ctcaacatac aatgctagtt 
               
               
                   
               
               
                 15901 
                 aaacagggtg atgattatgt gtaccttcct tacccagatc catcaagaat cctaggggcc 
               
               
                   
               
               
                 15961 
                 ggctgttttg tagatgatat cgtaaaaaca gatggtacac ttatgattga acggttcgtg 
               
               
                   
               
               
                 16021 
                 tctttagcta tagatgctta cccacttact aaacatccta atcaggagta tgctgatgtc 
               
               
                   
               
               
                 16081 
                 tttcatttgt acttacaata cataagaaag ctacatgatg agttaacagg acacatgtta 
               
               
                   
               
               
                 16141 
                 gacatgtatt ctgttatgct tactaatgat aacacttcaa ggtattggga acctgagttt 
               
               
                   
               
               
                 16201 
                 tatgaggcta tgtacacacc gcatacagtc ttacaggctg ttggggcttg tgttctttgc 
               
               
                   
               
               
                 16261 
                 aattcacaga cttcattaag atgtggtgct tgcatacgta gaccattctt atgttgtaaa 
               
               
                   
               
               
                 16321 
                 tgctgttacg accatgtcat atcaacatca cataaattag tcttgtctgt taatccgtat 
               
               
                   
               
               
                 16381 
                 gtttgcaatg ctccaggttg tgatgtcaca gatgtgactc aactttactt aggaggtatg 
               
               
                   
               
               
                 16441 
                 agctattatt gtaaatcaca taaaccaccc attagttttc cattgtgtgc taatggacaa 
               
               
                   
               
               
                 16501 
                 gtttttggtt tatataaaaa tacatgtgtt ggtagcgata atgttactga ctttaatgca 
               
               
                   
               
               
                 16561 
                 attgcaacat gtgactggac aaatgctggt gattacattt tagctaacac ctgtactgaa 
               
               
                   
               
               
                 16621 
                 agactcaagc tttttgcagc agaaacgctc aaagctactg aggagacatt taaactgtct 
               
               
                   
               
               
                 16681 
                 tatggtattg ctactgtacg tgaagtgctg tctgacagag aattacatct ttcatgggaa 
               
               
                   
               
               
                 16741 
                 gttggtaaac ctagaccacc acttaaccga aattatgtct ttactggtta tcgtgtaact 
               
               
                   
               
               
                 16801 
                 aaaaacagta aagtacaaat aggagagtac acctttgaaa aaggtgacta tggtgatgct 
               
               
                   
               
               
                 16861 
                 gttgtttacc gaggtacaac aacttacaaa ttaaatgttg gtgattattt tgtgctgaca 
               
               
                   
               
               
                 16921 
                 tcacatacag taatgccatt aagtgcacct acactagtgc cacaagagca ctatgttaga 
               
               
                   
               
               
                 16981 
                 attactggct tatacccaac actcaatatc tcagatgagt tttctagcaa tgttgcaaat 
               
               
                   
               
               
                 17041 
                 tatcaaaagg ttggtatgca aaagtattct acactccagg gaccacctgg tactggtaag 
               
               
                   
               
               
                 17101 
                 agtcattttg ctattggcct agctctctac tacccttctg ctcgcatagt gtatacagct 
               
               
                   
               
               
                 17161 
                 tgctctcatg ccgctgttga tgcactatgt gagaaggcat taaaatattt gcctatagat 
               
               
                   
               
               
                 17221 
                 aaatgtagta gaattatacc tgcacgtgct cgtgtagagt gttttgataa attcaaagtg 
               
               
                   
               
               
                 17281 
                 aattcaacat tagaacagta tgtcttttgt actgtaaatg cattgcctga gacgacagca 
               
               
                   
               
               
                 17341 
                 gatatagttg tctttgatga aatttcaatg gccacaaatt atgatttgag tgttgtcaat 
               
               
                   
               
               
                 17401 
                 gccagattac gtgctaagca ctatgtgtac attggcgacc ctgctcaatt acctgcacca 
               
               
                   
               
               
                 17461 
                 cgcacattgc taactaaggg cacactagaa ccagaatatt tcaattcagt gtgtagactt 
               
               
                   
               
               
                 17521 
                 atgaaaacta taggtccaga catgttcctc ggaacttgtc ggcgttgtcc tgctgaaatt 
               
               
                   
               
               
                 17581 
                 gttgacactg tgagtgcttt ggtttatgat aataagctta aagcacataa agacaaatca 
               
               
                   
               
               
                 17641 
                 gctcaatgct ttaaaatgtt ttataagggt gttatcacgc atgatgtttc atctgcaatt 
               
               
                   
               
               
                 17701 
                 aacaggccac aaataggcgt ggtaagagaa ttccttacac gtaaccctgc ttggagaaaa 
               
               
                   
               
               
                 17761 
                 gctgtcttta tttcacctta taattcacag aatgctgtag cctcaaagat tttgggacta 
               
               
                   
               
               
                 17821 
                 ccaactcaaa ctgttgattc atcacagggc tcagaatatg actatgtcat attcactcaa 
               
               
                   
               
               
                 17881 
                 accactgaaa cagctcactc ttgtaatgta aacagattta atgttgctat taccagagca 
               
               
                   
               
               
                 17941 
                 aaagtaggca tactttgcat aatgtctgat agagaccttt atgacaagtt gcaatttaca 
               
               
                   
               
               
                 18001 
                 agtcttgaaa ttccacgtag gaatgtggca actttacaag ctgaaaatgt aacaggactc 
               
               
                   
               
               
                 18061 
                 tttaaagatt gtagtaaggt aatcactggg ttacatccta cacaggcacc tacacacctc 
               
               
                   
               
               
                 18121 
                 agtgttgaca ctaaattcaa aactgaaggt ttatgtgttg acatacctgg catacctaag 
               
               
                   
               
               
                 18181 
                 gacatgacct atagaagact catctctatg atgggtttta aaatgaatta tcaagttaat 
               
               
                   
               
               
                 18241 
                 ggttacccta acatgtttat cacccgcgaa gaagctataa gacatgtacg tgcatggatt 
               
               
                   
               
               
                 18301 
                 ggcttcgatg tcgaggggtg tcatgctact agagaagctg ttggtaccaa tttaccttta 
               
               
                   
               
               
                 18361 
                 cagctaggtt tttctacagg tgttaaccta gttgctgtac ctacaggtta tgttgataca 
               
               
                   
               
               
                 18421 
                 cctaataata cagatttttc cagagttagt gctaaaccac cgcctggaga tcaatttaaa 
               
               
                   
               
               
                 18481 
                 cacctcatac cacttatgta caaaggactt ccttggaatg tagtgcgtat aaagattgta 
               
               
                   
               
               
                 18541 
                 caaatgttaa gtgacacact taaaaatctc tctgacagag tcgtatttgt cttatgggca 
               
               
                   
               
               
                 18601 
                 catggctttg agttgacatc tatgaagtat tttgtgaaaa taggacctga gcgcacctgt 
               
               
                   
               
               
                 18661 
                 tgtctatgtg atagacgtgc cacatgcttt tccactgctt cagacactta tgcctgttgg 
               
               
                   
               
               
                 18721 
                 catcattcta ttggatttga ttacgtctat aatccgttta tgattgatgt tcaacaatgg 
               
               
                   
               
               
                 18781 
                 ggttttacag gtaacctaca aagcaaccat gatctgtatt gtcaagtcca tggtaatgca 
               
               
                   
               
               
                 18841 
                 catgtagcta gttgtgatgc aatcatgact aggtgtctag ctgtccacga gtgctttgtt 
               
               
                   
               
               
                 18901 
                 aagcgtgttg actggactat tgaatatcct ataattggtg atgaactgaa gattaatgcg 
               
               
                   
               
               
                 18961 
                 gcttgtagaa aggttcaaca catggttgtt aaagctgcat tattagcaga caaattccca 
               
               
                   
               
               
                 19021 
                 gttcttcacg acattggtaa ccctaaagct attaagtgtg tacctcaagc tgatgtagaa 
               
               
                   
               
               
                 19081 
                 tggaagttct atgatgcaca gccttgtagt gacaaagctt ataaaataga agaattattc 
               
               
                   
               
               
                 19141 
                 tattcttatg ccacacattc tgacaaattc acagatggtg tatgcctatt ttggaattgc 
               
               
                   
               
               
                 19201 
                 aatgtcgata gatatcctgc taattccatt gtttgtagat ttgacactag agtgctatct 
               
               
                   
               
               
                 19261 
                 aaccttaact tgcctggttg tgatggtggc agtttgtatg taaataaaca tgcattccac 
               
               
                   
               
               
                 19321 
                 acaccagctt ttgataaaag tgcttttgtt aatttaaaac aattaccatt tttctattac 
               
               
                   
               
               
                 19381 
                 tctgacagtc catgtgagtc tcatggaaaa caagtagtgt cagatataga ttatgtacca 
               
               
                   
               
               
                 19441 
                 ctaaagtctg ctacgtgtat aacacgttgc aatttaggtg gtgctgtctg tagacatcat 
               
               
                   
               
               
                 19501 
                 gctaatgagt acagattgta tctcgatgct tataacatga tgatctcagc tggctttagc 
               
               
                   
               
               
                 19561 
                 ttgtgggttt acaaacaatt tgatacttat aacctctgga acacttttac aagacttcag 
               
               
                   
               
               
                 19621 
                 agtttagaaa atgtggcttt taatgttgta aataagggac actttgatgg acaacagggt 
               
               
                   
               
               
                 19681 
                 gaagtaccag tttctatcat taataacact gtttacacaa aagttgatgg tgttgatgta 
               
               
                   
               
               
                 19741 
                 gaattgtttg aaaataaaac aacattacct gttaatgtag catttgagct ttgggctaag 
               
               
                   
               
               
                 19801 
                 cgcaacatta aaccagtacc agaggtgaaa atactcaata atttgggtgt ggacattgct 
               
               
                   
               
               
                 19861 
                 gctaatactg tgatctggga ctacaaaaga gatgctccag cacatatatc tactattggt 
               
               
                   
               
               
                 19921 
                 gtttgttcta tgactgacat agccaagaaa ccaactgaaa cgatttgtgc accactcact 
               
               
                   
               
               
                 19981 
                 gtcttttttg atggtagagt tgatggtcaa gtagacttat ttagaaatgc ccgtaatggt 
               
               
                   
               
               
                 20041 
                 gttcttatta cagaaggtag tgttaaaggt ttacaaccat ctgtaggtcc caaacaagct 
               
               
                   
               
               
                 20101 
                 agtcttaatg gagtcacatt aattggagaa gccgtaaaaa cacagttcaa ttattataag 
               
               
                   
               
               
                 20161 
                 aaagttgatg gtgttgtcca acaattacct gaaacttact ttactcagag tagaaattta 
               
               
                   
               
               
                 20221 
                 caagaattta aacccaggag tcaaatggaa attgatttct tagaattagc tatggatgaa 
               
               
                   
               
               
                 20281 
                 ttcattgaac ggtataaatt agaaggctat gccttcgaac atatcgttta tggagatttt 
               
               
                   
               
               
                 20341 
                 agtcatagtc agttaggtgg tttacatcta ctgattggac tagctaaacg ttttaaggaa 
               
               
                   
               
               
                 20401 
                 tcaccttttg aattagaaga ttttattcct atggacagta cagttaaaaa ctatttcata 
               
               
                   
               
               
                 20461 
                 acagatgcgc aaacaggttc atctaagtgt gtgtgttctg ttattgattt attacttgat 
               
               
                   
               
               
                 20521 
                 gattttgttg aaataataaa atcccaagat ttatctgtag tttctaaggt tgtcaaagtg 
               
               
                   
               
               
                 20581 
                 actattgact atacagaaat ttcatttatg ctttggtgta aagatggcca tgtagaaaca 
               
               
                   
               
               
                 20641 
                 ttttacccaa aattacaatc tagtcaagcg tggcaaccgg gtgttgctat gcctaatctt 
               
               
                   
               
               
                 20701 
                 tacaaaatgc aaagaatgct attagaaaag tgtgaccttc aaaattatgg tgatagtgca 
               
               
                   
               
               
                 20761 
                 acattaccta aaggcataat gatgaatgtc gcaaaatata ctcaactgtg tcaatattta 
               
               
                   
               
               
                 20821 
                 aacacattaa cattagctgt accctataat atgagagtta tacattttgg tgctggttct 
               
               
                   
               
               
                 20881 
                 gataaaggag ttgcaccagg tacagctgtt ttaagacagt ggttgcctac gggtacgctg 
               
               
                   
               
               
                 20941 
                 cttgtcgatt cagatcttaa tgactttgtc tctgatgcag attcaacttt gattggtgat 
               
               
                   
               
               
                 21001 
                 tgtgcaactg tacatacagc taataaatgg gatctcatta ttagtgatat gtacgaccct 
               
               
                   
               
               
                 21061 
                 aagactaaaa atgttacaaa agaaaatgac tctaaagagg gttttttcac ttacatttgt 
               
               
                   
               
               
                 21121 
                 gggtttatac aacaaaagct agctcttgga ggttccgtgg ctataaagat aacagaacat 
               
               
                   
               
               
                 21181 
                 tcttggaatg ctgatcttta taagctcatg ggacacttcg catggtggac agcctttgtt 
               
               
                   
               
               
                 21241 
                 actaatgtga atgcgtcatc atctgaagca tttttaattg gatgtaatta tcttggcaaa 
               
               
                   
               
               
                 21301 
                 ccacgcgaac aaatagatgg ttatgtcatg catgcaaatt acatattttg gaggaataca 
               
               
                   
               
               
                 21361 
                 aatccaattc agttgtcttc ctattcttta tttgacatga gtaaatttcc ccttaaatta 
               
               
                   
               
               
                 21421 
                 aggggtactg ctgttatgtc tttaaaagaa ggtcaaatca atgatatgat tttatctctt 
               
               
                   
               
               
                 21481 
                 cttagtaaag gtagacttat aattagagaa aacaacagag ttgttatttc tagtgatgtt 
               
               
                   
               
               
                 21541 
                 cttgttaaca actaaacgaa caatgtttgt ttttcttgtt ttattgccac tagtctctag 
               
               
                   
               
               
                 21601 
                 tcagtgtgtt aatcttacaa ccagaactca attaccccct gcatacacta attctttcac 
               
               
                   
               
               
                 21661 
                 acgtggtgtt tattaccctg acaaagtttt cagatcctca gttttacatt caactcagga 
               
               
                   
               
               
                 21721 
                 cttgttctta cctttctttt ccaatgttac ttggttccat gctatacatg tctctgggac 
               
               
                   
               
               
                 21781 
                 caatggtact aagaggtttg ataaccctgt cctaccattt aatgatggtg tttattttgc 
               
               
                   
               
               
                 21841 
                 ttccactgag aagtctaaca taataagagg ctggattttt ggtactactt tagattcgaa 
               
               
                   
               
               
                 21901 
                 gacccagtcc ctacttattg ttaataacgc tactaatgtt gttattaaag tctgtgaatt 
               
               
                   
               
               
                 21961 
                 tcaattttgt aatgatccat ttttgggtgt ttattaccac aaaaacaaca aaagttggat 
               
               
                   
               
               
                 22021 
                 ggaaagtgag ttcagagttt attctagtgc gaataattgc acttttgaat atgtctctca 
               
               
                   
               
               
                 22081 
                 gccttttctt atggaccttg aaggaaaaca gggtaatttc aaaaatctta gggaatttgt 
               
               
                   
               
               
                 22141 
                 gtttaagaat attgatggtt attttaaaat atattctaag cacacgccta ttaatttagt 
               
               
                   
               
               
                 22201 
                 gcgtgatctc cctcagggtt tttcggcttt agaaccattg gtagatttgc caataggtat 
               
               
                   
               
               
                 22261 
                 taacatcact aggtttcaaa ctttacttgc tttacataga agttatttga ctcctggtga 
               
               
                   
               
               
                 22321 
                 ttcttcttca ggttggacag ctggtgctgc agcttattat gtgggttatc ttcaacctag 
               
               
                   
               
               
                 22381 
                 gacttttcta ttaaaatata atgaaaatgg aaccattaca gatgctgtag actgtgcact 
               
               
                   
               
               
                 22441 
                 tgaccctctc tcagaaacaa agtgtacgtt gaaatccttc actgtagaaa aaggaatcta 
               
               
                   
               
               
                 22501 
                 tcaaacttct aactttagag tccaaccaac agaatctatt gttagatttc ctaatattac 
               
               
                   
               
               
                 22561 
                 aaacttgtgc ccttttggtg aagtttttaa cgccaccaga tttgcatctg tttatgcttg 
               
               
                   
               
               
                 22621 
                 gaacaggaag agaatcagca actgtgttgc tgattattct gtcctatata attccgcatc 
               
               
                   
               
               
                 22681 
                 attttccact tttaagtgtt atggagtgtc tcctactaaa ttaaatgatc tctgctttac 
               
               
                   
               
               
                 22741 
                 taatgtctat gcagattcat ttgtaattag aggtgatgaa gtcagacaaa tcgctccagg 
               
               
                   
               
               
                 22801 
                 gcaaactgga aagattgctg attataatta taaattacca gatgatttta caggctgcgt 
               
               
                   
               
               
                 22861 
                 tatagcttgg aattctaaca atcttgattc taaggttggt ggtaattata attacctgta 
               
               
                   
               
               
                 22921 
                 tagattgttt aggaagtcta atctcaaacc ttttgagaga gatatttcaa ctgaaatcta 
               
               
                   
               
               
                 22981 
                 tcaggccggt agcacacctt gtaatggtgt tgaaggtttt aattgttact ttcctttaca 
               
               
                   
               
               
                 23041 
                 atcatatggt ttccaaccca ctaatggtgt tggttaccaa ccatacagag tagtagtact 
               
               
                   
               
               
                 23101 
                 ttcttttgaa cttctacatg caccagcaac tgtttgtgga cctaaaaagt ctactaattt 
               
               
                   
               
               
                 23161 
                 ggttaaaaac aaatgtgtca atttcaactt caatggttta acaggcacag gtgttcttac 
               
               
                   
               
               
                 23221 
                 tgagtctaac aaaaagtttc tgcctttcca acaatttggc agagacattg ctgacactac 
               
               
                   
               
               
                 23281 
                 tgatgctgtc cgtgatccac agacacttga gattcttgac attacaccat gttcttttgg 
               
               
                   
               
               
                 23341 
                 tggtgtcagt gttataacac caggaacaaa tacttctaac caggttgctg ttctttatca 
               
               
                   
               
               
                 23401 
                 ggatgttaac tgcacagaag tccctgttgc tattcatgca gatcaactta ctcctacttg 
               
               
                   
               
               
                 23461 
                 gcgtgtttat tctacaggtt ctaatgtttt tcaaacacgt gcaggctgtt taataggggc 
               
               
                   
               
               
                 23521 
                 tgaacatgtc aacaactcat atgagtgtga catacccatt ggtgcaggta tatgcgctag 
               
               
                   
               
               
                 23581 
                 ttatcagact cagactaatt ctcctcggcg ggcacgtagt gtagctagtc aatccatcat 
               
               
                   
               
               
                 23641 
                 tgcctacact atgtcacttg gtgcagaaaa ttcagttgct tactctaata actctattgc 
               
               
                   
               
               
                 23701 
                 catacccaca aattttacta ttagtgttac cacagaaatt ctaccagtgt ctatgaccaa 
               
               
                   
               
               
                 23761 
                 gacatcagta gattgtacaa tgtacatttg tggtgattca actgaatgca gcaatctttt 
               
               
                   
               
               
                 23821 
                 gttgcaatat ggcagttttt gtacacaatt aaaccgtgct ttaactggaa tagctgttga 
               
               
                   
               
               
                 23881 
                 acaagacaaa aacacccaag aagtttttgc acaagtcaaa caaatttaca aaacaccacc 
               
               
                   
               
               
                 23941 
                 aattaaagat tttggtggtt ttaatttttc acaaatatta ccagatccat caaaaccaag 
               
               
                   
               
               
                 24001 
                 caagaggtca tttattgaag atctactttt caacaaagtg acacttgcag atgctggctt 
               
               
                   
               
               
                 24061 
                 catcaaacaa tatggtgatt gccttggtga tattgctgct agagacctca tttgtgcaca 
               
               
                   
               
               
                 24121 
                 aaagtttaac ggccttactg ttttgccacc tttgctcaca gatgaaatga ttgctcaata 
               
               
                   
               
               
                 24181 
                 cacttctgca ctgttagcgg gtacaatcac ttctggttgg acctttggtg caggtgctgc 
               
               
                   
               
               
                 24241 
                 attacaaata ccatttgcta tgcaaatggc ttataggttt aatggtattg gagttacaca 
               
               
                   
               
               
                 24301 
                 gaatgttctc tatgagaacc aaaaattgat tgccaaccaa tttaatagtg ctattggcaa 
               
               
                   
               
               
                 24361 
                 aattcaagac tcactttctt ccacagcaag tgcacttgga aaacttcaag atgtggtcaa 
               
               
                   
               
               
                 24421 
                 ccaaaatgca caagctttaa acacgcttgt taaacaactt agctccaatt ttggtgcaat 
               
               
                   
               
               
                 24481 
                 ttcaagtgtt ttaaatgata tcctttcacg tcttgacaaa gttgaggctg aagtgcaaat 
               
               
                   
               
               
                 24541 
                 tgataggttg atcacaggca gacttcaaag tttgcagaca tatgtgactc aacaattaat 
               
               
                   
               
               
                 24601 
                 tagagctgca gaaatcagag cttctgctaa tcttgctgct actaaaatgt cagagtgtgt 
               
               
                   
               
               
                 24661 
                 acttggacaa tcaaaaagag ttgatttttg tggaaagggc tatcatctta tgtccttccc 
               
               
                   
               
               
                 24721 
                 tcagtcagca cctcatggtg tagtcttctt gcatgtgact tatgtccctg cacaagaaaa 
               
               
                   
               
               
                 24781 
                 gaacttcaca actgctcctg ccatttgtca tgatggaaaa gcacactttc ctcgtgaagg 
               
               
                   
               
               
                 24841 
                 tgtctttgtt tcaaatggca cacactggtt tgtaacacaa aggaattttt atgaaccaca 
               
               
                   
               
               
                 24901 
                 aatcattact acagacaaca catttgtgtc tggtaactgt gatgttgtaa taggaattgt 
               
               
                   
               
               
                 24961 
                 caacaacaca gtttatgatc ctttgcaacc tgaattagac tcattcaagg aggagttaga 
               
               
                   
               
               
                 25021 
                 taaatatttt aagaatcata catcaccaga tgttgattta ggtgacatct ctggcattaa 
               
               
                   
               
               
                 25081 
                 tgcttcagtt gtaaacattc aaaaagaaat tgaccgcctc aatgaggttg ccaagaattt 
               
               
                   
               
               
                 25141 
                 aaatgaatct ctcatcgatc tccaagaact tggaaagtat gagcagtata taaaatggcc 
               
               
                   
               
               
                 25201 
                 atggtacatt tggctaggtt ttatagctgg cttgattgcc atagtaatgg tgacaattat 
               
               
                   
               
               
                 25261 
                 gctttgctgt atgaccagtt gctgtagttg tctcaagggc tgttgttctt gtggatcctg 
               
               
                   
               
               
                 25321 
                 ctgcaaattt gatgaagacg actctgagcc agtgctcaaa ggagtcaaat tacattacac 
               
               
                   
               
               
                 25381 
                 ataaacgaac ttatggattt gtttatgaga atcttcacaa ttggaactgt aactttgaag 
               
               
                   
               
               
                 25441 
                 caaggtgaaa tcaaggatgc tactccttca gattttgttc gcgctactgc aacgataccg 
               
               
                   
               
               
                 25501 
                 atacaagcct cactcccttt cggatggctt attgttggcg ttgcacttct tgctgttttt 
               
               
                   
               
               
                 25561 
                 cagagcgctt ccaaaatcat aaccctcaaa aagagatggc aactagcact ctccaagggt 
               
               
                   
               
               
                 25621 
                 gttcactttg tttgcaactt gctgttgttg tttgtaacag tttactcaca ccttttgctc 
               
               
                   
               
               
                 25681 
                 gttgctgctg gccttgaagc cccttttctc tatctttatg ctttagtcta cttcttgcag 
               
               
                   
               
               
                 25741 
                 agtataaact ttgtaagaat aataatgagg ctttggcttt gctggaaatg ccgttccaaa 
               
               
                   
               
               
                 25801 
                 aacccattac tttatgatgc caactatttt ctttgctggc atactaattg ttacgactat 
               
               
                   
               
               
                 25861 
                 tgtatacctt acaatagtgt aacttcttca attgtcatta cttcaggtga tggcacaaca 
               
               
                   
               
               
                 25921 
                 agtcctattt ctgaacatga ctaccagatt ggtggttata ctgaaaaatg ggaatctgga 
               
               
                   
               
               
                 25981 
                 gtaaaagact gtgttgtatt acacagttac ttcacttcag actattacca gctgtactca 
               
               
                   
               
               
                 26041 
                 actcaattga gtacagacac tggtgttgaa catgttacct tcttcatcta caataaaatt 
               
               
                   
               
               
                 26101 
                 gttgatgagc ctgaagaaca tgtccaaatt cacacaatcg acggttcatc cggagttgtt 
               
               
                   
               
               
                 26161 
                 aatccagtaa tggaaccaat ttatgatgaa ccgacgacga ctactagcgt gcctttgtaa 
               
               
                   
               
               
                 26221 
                 gcacaagctg atgagtacga acttatgtac tcattcgttt cggaagagac aggtacgtta 
               
               
                   
               
               
                 26281 
                 atagttaata gcgtacttct ttttcttgct ttcgtggtat tcttgctagt tacactagcc 
               
               
                   
               
               
                 26341 
                 atccttactg cgcttcgatt gtgtgcgtac tgctgcaata ttgttaacgt gagtcttgta 
               
               
                   
               
               
                 26401 
                 aaaccttctt tttacgttta ctctcgtgtt aaaaatctga attcttctag agttcctgat 
               
               
                   
               
               
                 26461 
                 cttctggtct aaacgaacta aatattatat tagtttttct gtttggaact ttaattttag 
               
               
                   
               
               
                 26521 
                 ccatggcaga ttccaacggt actattaccg ttgaagagct taaaaagctc cttgaacaat 
               
               
                   
               
               
                 26581 
                 ggaacctagt aataggtttc ctattcctta catggatttg tcttctacaa tttgcctatg 
               
               
                   
               
               
                 26641 
                 ccaacaggaa taggtttttg tatataatta agttaatttt cctctggctg ttatggccag 
               
               
                   
               
               
                 26701 
                 taactttagc ttgttttgtg cttgctgctg tttacagaat aaattggatc accggtggaa 
               
               
                   
               
               
                 26761 
                 ttgctatcgc aatggcttgt cttgtaggct tgatgtggct cagctacttc attgcttctt 
               
               
                   
               
               
                 26821 
                 tcagactgtt tgcgcgtacg cgttccatgt ggtcattcaa tccagaaact aacattcttc 
               
               
                   
               
               
                 26881 
                 tcaacgtgcc actccatggc actattctga ccagaccgct tctagaaagt gaactcgtaa 
               
               
                   
               
               
                 26941 
                 tcggagctgt gatccttcgt ggacatcttc gtattgctgg acaccatcta ggacgctgtg 
               
               
                   
               
               
                 27001 
                 acatcaagga cctgcctaaa gaaatcactg ttgctacatc acgaacgctt tcttattaca 
               
               
                   
               
               
                 27061 
                 aattgggagc ttcgcagcgt gtagcaggtg actcaggttt tgctgcatac agtcgctaca 
               
               
                   
               
               
                 27121 
                 ggattggcaa ctataaatta aacacagacc attccagtag cagtgacaat attgctttgc 
               
               
                   
               
               
                 27181 
                 ttgtacagta agtgacaaca gatgtttcat ctcgttgact ttcaggttac tatagcagag 
               
               
                   
               
               
                 27241 
                 atattactaa ttattatgag gacttttaaa gtttccattt ggaatcttga ttacatcata 
               
               
                   
               
               
                 27301 
                 aacctcataa ttaaaaattt atctaagtca ctaactgaga ataaatattc tcaattagat 
               
               
                   
               
               
                 27361 
                 gaagagcaac caatggagat tgattaaacg aacatgaaaa ttattctttt cttggcactg 
               
               
                   
               
               
                 27421 
                 ataacactcg ctacttgtga gctttatcac taccaagagt gtgttagagg tacaacagta 
               
               
                   
               
               
                 27481 
                 cttttaaaag aaccttgctc ttctggaaca tacgagggca attcaccatt tcatcctcta 
               
               
                   
               
               
                 27541 
                 gctgataaca aatttgcact gacttgcttt agcactcaat ttgcttttgc ttgtcctgac 
               
               
                   
               
               
                 27601 
                 ggcgtaaaac acgtctatca gttacgtgcc agatcagttt cacctaaact gttcatcaga 
               
               
                   
               
               
                 27661 
                 caagaggaag ttcaagaact ttactctcca atttttctta ttgttgcggc aatagtgttt 
               
               
                   
               
               
                 27721 
                 ataacacttt gcttcacact caaaagaaag acagaatgat tgaactttca ttaattgact 
               
               
                   
               
               
                 27781 
                 tctatttgtg ctttttagcc tttctgctat tccttgtttt aattatgctt attatctttt 
               
               
                   
               
               
                 27841 
                 ggttctcact tgaactgcaa gatcataatg aaacttgtca cgcctaaacg aacatgaaat 
               
               
                   
               
               
                 27901 
                 ttcttgtttt cttaggaatc atcacaactg tagctgcatt tcaccaagaa tgtagtttac 
               
               
                   
               
               
                 27961 
                 agtcatgtac tcaacatcaa ccatatgtag ttgatgaccc gtgtcctatt cacttctatt 
               
               
                   
               
               
                 28021 
                 ctaaatggta tattagagta ggagctagaa aatcagcacc tttaattgaa ttgtgcgtgg 
               
               
                   
               
               
                 28081 
                 atgaggctgg ttctaaatca cccattcagt acatcgatat cggtaattat acagtttcct 
               
               
                   
               
               
                 28141 
                 gtttaccttt tacaattaat tgccaggaac ctaaattggg tagtcttgta gtgcgttgtt 
               
               
                   
               
               
                 28201 
                 cgttctatga agacttttta gagtatcatg acgttcgtgt tgttttagat ttcatctaaa 
               
               
                   
               
               
                 28261 
                 cgaacaaact aaaatgtctg ataatggacc ccaaaatcag cgaaatgcac cccgcattac 
               
               
                   
               
               
                 28321 
                 gtttggtgga ccctcagatt caactggcag taaccagaat ggagaacgca gtggggcgcg 
               
               
                   
               
               
                 28381 
                 atcaaaacaa cgtcggcccc aaggtttacc caataatact gcgtcttggt tcaccgctct 
               
               
                   
               
               
                 28441 
                 cactcaacat ggcaaggaag accttaaatt ccctcgagga caaggcgttc caattaacac 
               
               
                   
               
               
                 28501 
                 caatagcagt ccagatgacc aaattggcta ctaccgaaga gctaccagac gaattcgtgg 
               
               
                   
               
               
                 28561 
                 tggtgacggt aaaatgaaag atctcagtcc aagatggtat ttctactacc taggaactgg 
               
               
                   
               
               
                 28621 
                 gccagaagct ggacttccct atggtgctaa caaagacggc atcatatggg ttgcaactga 
               
               
                   
               
               
                 28681 
                 gggagccttg aatacaccaa aagatcacat tggcacccgc aatcctgcta acaatgctgc 
               
               
                   
               
               
                 28741 
                 aatcgtgcta caacttcctc aaggaacaac attgccaaaa ggcttctacg cagaagggag 
               
               
                   
               
               
                 28801 
                 cagaggcggc agtcaagcct cttctcgttc ctcatcacgt agtcgcaaca gttcaagaaa 
               
               
                   
               
               
                 28861 
                 ttcaactcca ggcagcagta ggggaacttc tcctgctaga atggctggca atggcggtga 
               
               
                   
               
               
                 28921 
                 tgctgctctt gctttgctgc tgcttgacag attgaaccag cttgagagca aaatgtctgg 
               
               
                   
               
               
                 28981 
                 taaaggccaa caacaacaag gccaaactgt cactaagaaa tctgctgctg aggcttctaa 
               
               
                   
               
               
                 29041 
                 gaagcctcgg caaaaacgta ctgccactaa agcatacaat gtaacacaag ctttcggcag 
               
               
                   
               
               
                 29101 
                 acgtggtcca gaacaaaccc aaggaaattt tggggaccag gaactaatca gacaaggaac 
               
               
                   
               
               
                 29161 
                 tgattacaaa cattggccgc aaattgcaca atttgccccc agcgcttcag cgttcttcgg 
               
               
                   
               
               
                 29221 
                 aatgtcgcgc attggcatgg aagtcacacc ttcgggaacg tggttgacct acacaggtgc 
               
               
                   
               
               
                 29281 
                 catcaaattg gatgacaaag atccaaattt caaagatcaa gtcattttgc tgaataagca 
               
               
                   
               
               
                 29341 
                 tattgacgca tacaaaacat tcccaccaac agagcctaaa aaggacaaaa agaagaaggc 
               
               
                   
               
               
                 29401 
                 tgatgaaact caagccttac cgcagagaca gaagaaacag caaactgtga ctcttcttcc 
               
               
                   
               
               
                 29461 
                 tgctgcagat ttggatgatt tctccaaaca attgcaacaa tccatgagca gtgctgactc 
               
               
                   
               
               
                 29521 
                 aactcaggcc taaactcatg cagaccacac aaggcagatg ggctatataa acgttttcgc 
               
               
                   
               
               
                 29581 
                 ttttccgttt acgatatata gtctactctt gtgcagaatg aattctcgta actacatagc 
               
               
                   
               
               
                 29641 
                 acaagtagat gtagttaact ttaatctcac atagcaatct ttaatcagtg tgtaacatta 
               
               
                   
               
               
                 29701 
                 gggaggactt gaaagagcca ccacattttc accgaggcca cgcggagtac gatcgagtgt 
               
               
                   
               
               
                 29761 
                 acagtgaaca atgctaggga gagctgccta tatggaagag ccctaatgtg taaaattaat 
               
               
                   
               
               
                 29821 
                 tttagtagtg ctatccccat gtgattttaa tagcttctta ggagaatgac aaaaaaaaaa 
               
               
                   
               
               
                 29881 
                 aaaaaaaaaa aaaaaaaaaa aaa