3ab358e6d215e0c2af201f60053888cd  Aran_et_al_TCRs_2023.pdf
f7cb7db33e57ee060e4daa5a371b3881dafc95e2  Aran_et_al_TCRs_2023.pdf
ca164f51de33ff1bcc25e4d175a85cbe77aa3e46ccaf659d31952c83c634fe9d  Aran_et_al_TCRs_2023.pdf

Title:           Analysis of tumor infiltrating CD4+ and CD8+ CDR3 sequences reveals shared features putatively associated to the anti-tumor immune response
Subject:         Tumor-infiltrating lymphocytes (TILs) have predictive and prognostic value in breast cancer (BC) and exert a protective function against tumor growth, indicating that it is susceptible to treatment using adoptive cell transfer of TILs or T cell receptor (TCR)-based therapies.
Keywords:        tumor-infiltrating lymphocytes, CD4+ T cells, CD8+ T cells, T cell receptor, breast cancer
Author:          Andrea Aran
CreationDate:    Tue Aug  1 09:06:53 2023 CEST
ModDate:         Tue Aug  1 09:52:07 2023 CEST
Custom Metadata: no
Metadata Stream: yes
Tagged:          no
UserProperties:  no
Suspects:        no
Form:            AcroForm
JavaScript:      no
Pages:           15
Encrypted:       no
Page size:       595.389 x 841.663 pts (A4)
Page rot:        0
File size:       2055639 bytes
Optimized:       no
PDF version:     1.6


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
DANPCE+AdvTTd3a5f740                 Type 1C           WinAnsi          yes yes no     614  0
DANPEN+AdvTT2c8ce45a+fb              Type 1C           Custom           yes yes yes    632  0
DAODKD+AdvTT9b12cd41+01              Type 1C           MacRoman         yes yes no     639  0
DAODLE+AdvTTd168d80a.I               Type 1C           WinAnsi          yes yes no     642  0
DANPDF+AdvTTd3a5f740+fb              Type 1C           Custom           yes yes yes    615  0
DANPDG+AdvPSA18C                     Type 1C           WinAnsi          yes yes no     616  0
DANPDH+AdvTTd3a5f740+01              Type 1C           MacRoman         yes yes no     617  0
DANPDI+AdvTT9b12cd41                 Type 1C           WinAnsi          yes yes no     618  0
DANPDJ+AdvTT9b12cd41+20              Type 1C           WinAnsi          yes yes no     619  0
DANPDK+AdvPSA323                     Type 1C           WinAnsi          yes yes no     620  0
DANPDL+AdvTT2c8ce45a                 Type 1C           WinAnsi          yes yes no     630  0
DANPDM+AdvTT9b12cd41+fb              Type 1C           Custom           yes yes yes    631  0
DAODPD+AdvOT1ef757c0                 Type 1C           WinAnsi          yes yes no     322  0
DAODPE+AdvOT1ef757c0+fb              Type 1C           Custom           yes yes yes    329  0
DAOEAF+AdvOT1ef757c0+20              Type 1C           WinAnsi          yes yes no     325  0
DAOEDF+AdvOTd877c31c+21              Type 1C           WinAnsi          yes yes no     332  0
DAOEDG+AdvOT3f84ef53                 Type 1C           WinAnsi          yes yes no     333  0
DAOLMI+AdvOT7d6df7ab.I               Type 1C           WinAnsi          yes yes no     338  0
DAPFAA+HelveticaNeueLTStd-Bd         Type 1C           WinAnsi          yes yes no     339  0
DAPFOM+AdvTT9b12cd41+22              Type 1C           Custom           yes yes yes    341  0
DBCGAF+AdvOT46dcae81                 Type 1C           WinAnsi          yes yes no     352  0
DBCGFE+AdvTT58d178b9+03              Type 1C           Custom           yes yes yes    353  0
DBCGFF+AdvTTd3a5f740+20              Type 1C           WinAnsi          yes yes no     357  0
DBCGIF+AdvOT1ef757c0+01              Type 1C           MacRoman         yes yes no     359  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2025-01-22 02:42:33 CET
 RepresentationInformation: Aran_et_al_TCRs_2023.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2025-01-21 09:35:58 CET
  Size: 2055639
  Format: PDF
  Version: 1.6
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  PDFMetadata: 
   Objects: 0
   FreeObjects: 10
   IncrementalUpdates: 0
   DocumentCatalog: 
    PageLayout: SinglePage
    PageMode: UseOutlines
    Outlines: 
     Item: 
      Title: Analysis of tumor infiltrating CD4+ and CD8+ CDR3 sequences reveals shared features putatively associated to the anti-tumor immune response
      Destination: bmark_-180998973
      Children: 
       Item: 
        Title: 1 Introduction
        Destination: s1
       Item: 
        Title: 2 Material and methods
        Destination: s2
        Children: 
         Item: 
          Title: 2.1 Breast cancer TILs samples
          Destination: s2_1
         Item: 
          Title: 2.2 Peripheral T cell samples from healthy donors
          Destination: s2_2
         Item: 
          Title: 2.3 T cell cultures and expansions
          Destination: s2_3
         Item: 
          Title: 2.4 Flow cytometry and cell sorter
          Destination: s2_4
         Item: 
          Title: 2.5 TCR library preparation
          Destination: s2_5
         Item: 
          Title: 2.6 TCR repertoire analysis
          Destination: s2_6
         Item: 
          Title: 2.7 Statistical analysis and figures
          Destination: s2_7
       Item: 
        Title: 3 Results
        Destination: s3
        Children: 
         Item: 
          Title: 3.1 Analysis of CDR3 differences between CD4+ and CD8+ TILs and peripheral T cells from healthy donors
          Destination: s3_1
         Item: 
          Title: 3.2 Diversity analysis of CD4+ TCR from TILs reveals a restricted repertoire
          Destination: s3_2
         Item: 
          Title: 3.3 The lower diversity found in CD4+ TILs could not be attributed to the expansion of public sequences or to higher convergence
          Destination: s3_3
         Item: 
          Title: 3.4 Expanded CD4+ T-TILs present similar TCRs with conserved CDR3aa motifs shared among studied patients
          Destination: s3_4
         Item: 
          Title: 3.5 TCR motifs may be used to identify tumor-reactive CD4+ T cells
          Destination: s3_5
       Item: 
        Title: 4 Discussion
        Destination: s4
       Item: 
        Title: Data availability statement
        Destination: s5
       Item: 
        Title: Ethics statement
        Destination: s6
       Item: 
        Title: Author contributions
        Destination: s7
       Item: 
        Title: Funding
        Destination: bmark_1865464027
       Item: 
        Title: Acknowledgments
        Destination: bmark_-366698314
       Item: 
        Title: Supplementary material
        Destination: bmark_632582120
       Item: 
        Title: References
        Destination: bmark_2090415954
   Filters: 
    FilterPipeline: FlateDecode
    FilterPipeline: DCTDecode
   Images: 
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 2919
      ImageHeight: 577
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 2428
      ImageHeight: 1368
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1482
      ImageHeight: 2468
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 2170
      ImageHeight: 1521
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1863
      ImageHeight: 2344
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1402
      ImageHeight: 1356
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1798
      ImageHeight: 2258
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 2120
      ImageHeight: 1473
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
   Fonts: 
    Type1: 
     Font: 
      BaseFont: DBCGAF+AdvOT46dcae81
      FontSubset: true
      FirstChar: 43
      LastChar: 121
      FontDescriptor: 
       FontName: DBCGAF+AdvOT46dcae81
       Flags: Nonsymbolic
       FontBBox: -41, -250, 833, 875
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DBCGFE+AdvTT58d178b9+03
      FontSubset: true
      FirstChar: 0
      LastChar: 0
      FontDescriptor: 
       FontName: DBCGFE+AdvTT58d178b9+03
       Flags: Symbolic
       FontBBox: -645, -354, 916, 895
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DAODLE+AdvTTd168d80a.I
      FontSubset: true
      FirstChar: 46
      LastChar: 118
      FontDescriptor: 
       FontName: DAODLE+AdvTTd168d80a.I
       Flags: Serif, Nonsymbolic
       FontBBox: -145, -208, 968, 875
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAODPD+AdvOT1ef757c0
      FontSubset: true
      FirstChar: 35
      LastChar: 252
      FontDescriptor: 
       FontName: DAODPD+AdvOT1ef757c0
       Flags: Serif, Nonsymbolic
       FontBBox: -20, -250, 947, 854
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAOEAF+AdvOT1ef757c0+20
      FontSubset: true
      FirstChar: 146
      LastChar: 151
      FontDescriptor: 
       FontName: DAOEAF+AdvOT1ef757c0+20
       Flags: Nonsymbolic
       FontBBox: -135, -187, 1010, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DBCGFF+AdvTTd3a5f740+20
      FontSubset: true
      FirstChar: 146
      LastChar: 146
      FontDescriptor: 
       FontName: DBCGFF+AdvTTd3a5f740+20
       Flags: Nonsymbolic
       FontBBox: -114, -166, 1062, 864
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DANPCE+AdvTTd3a5f740
      FontSubset: true
      FirstChar: 42
      LastChar: 232
      FontDescriptor: 
       FontName: DANPCE+AdvTTd3a5f740
       Flags: Serif, Nonsymbolic
       FontBBox: -52, -208, 916, 885
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DANPDF+AdvTTd3a5f740+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: DANPDF+AdvTTd3a5f740+fb
       Flags: Symbolic
       FontBBox: 0, 0, 906, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DBCGIF+AdvOT1ef757c0+01
      FontSubset: true
      FirstChar: 245
      LastChar: 245
      FontDescriptor: 
       FontName: DBCGIF+AdvOT1ef757c0+01
       Flags: Serif, Nonsymbolic
       FontBBox: -20, -250, 947, 854
       FontFile3: true
      Encoding: MacRomanEncoding
     Font: 
      BaseFont: DANPDG+AdvPSA18C
      FontSubset: true
      FirstChar: 180
      LastChar: 180
      FontDescriptor: 
       FontName: DANPDG+AdvPSA18C
       Flags: Nonsymbolic
       FontBBox: -156, -208, 1125, 802
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DANPDH+AdvTTd3a5f740+01
      FontSubset: true
      FirstChar: 245
      LastChar: 245
      FontDescriptor: 
       FontName: DANPDH+AdvTTd3a5f740+01
       Flags: Nonsymbolic
       FontBBox: -52, -208, 947, 885
       FontFile3: true
      Encoding: MacRomanEncoding
     Font: 
      BaseFont: DAODPE+AdvOT1ef757c0+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: DAODPE+AdvOT1ef757c0+fb
       Flags: Symbolic
       FontBBox: 0, -10, 781, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DANPDI+AdvTT9b12cd41
      FontSubset: true
      FirstChar: 40
      LastChar: 242
      FontDescriptor: 
       FontName: DANPDI+AdvTT9b12cd41
       Flags: Serif, Nonsymbolic
       FontBBox: -52, -208, 906, 875
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DANPDJ+AdvTT9b12cd41+20
      FontSubset: true
      FirstChar: 146
      LastChar: 148
      FontDescriptor: 
       FontName: DANPDJ+AdvTT9b12cd41+20
       Flags: Nonsymbolic
       FontBBox: -114, -166, 1010, 864
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DANPDK+AdvPSA323
      FontSubset: true
      FirstChar: 180
      LastChar: 180
      FontDescriptor: 
       FontName: DANPDK+AdvPSA323
       Flags: Nonsymbolic
       FontBBox: -156, -239, 1104, 770
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAOEDF+AdvOTd877c31c+21
      FontSubset: true
      FirstChar: 153
      LastChar: 153
      FontDescriptor: 
       FontName: DAOEDF+AdvOTd877c31c+21
       Flags: Nonsymbolic
       FontBBox: -10, -250, 1145, 864
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAOEDG+AdvOT3f84ef53
      FontSubset: true
      FirstChar: 97
      LastChar: 109
      FontDescriptor: 
       FontName: DAOEDG+AdvOT3f84ef53
       Flags: Nonsymbolic
       FontBBox: -177, -291, 1083, 1000
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAOLMI+AdvOT7d6df7ab.I
      FontSubset: true
      FirstChar: 40
      LastChar: 121
      FontDescriptor: 
       FontName: DAOLMI+AdvOT7d6df7ab.I
       Flags: Nonsymbolic
       FontBBox: -135, -250, 1000, 854
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAPFAA+HelveticaNeueLTStd-Bd
      FontSubset: true
      FirstChar: 65
      LastChar: 70
      FontDescriptor: 
       FontName: DAPFAA+HelveticaNeueLTStd-Bd
       Flags: Nonsymbolic, ForceBold
       FontBBox: -166, -218, 1078, 975
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DAPFOM+AdvTT9b12cd41+22
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: DAPFOM+AdvTT9b12cd41+22
       Flags: Symbolic
       FontBBox: 0, -156, 552, 697
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DANPDL+AdvTT2c8ce45a
      FontSubset: true
      FirstChar: 40
      LastChar: 121
      FontDescriptor: 
       FontName: DANPDL+AdvTT2c8ce45a
       Flags: Serif, Nonsymbolic
       FontBBox: -52, -208, 947, 895
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: DANPDM+AdvTT9b12cd41+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: DANPDM+AdvTT9b12cd41+fb
       Flags: Symbolic
       FontBBox: 0, 0, 854, 697
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DANPEN+AdvTT2c8ce45a+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: DANPEN+AdvTT2c8ce45a+fb
       Flags: Symbolic
       FontBBox: 0, 0, 947, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DAODKD+AdvTT9b12cd41+01
      FontSubset: true
      FirstChar: 245
      LastChar: 245
      FontDescriptor: 
       FontName: DAODKD+AdvTT9b12cd41+01
       Flags: Nonsymbolic
       FontBBox: -52, -208, 958, 875
       FontFile3: true
      Encoding: MacRomanEncoding
   XMP: <x:xmpmeta xmlns:x="adobe:ns:meta/" x:xmptk="Adobe XMP Core 5.2-c001 63.139439, 2010/09/27-13:37:26        ">
   <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about=""
            xmlns:dc="http://purl.org/dc/elements/1.1/">
         <dc:format>application/pdf</dc:format>
         <dc:creator>
            <rdf:Seq>
               <rdf:li>Andrea Aran</rdf:li>
               <rdf:li>Gonzalo Lázaro</rdf:li>
               <rdf:li>Vicente Marco</rdf:li>
               <rdf:li>Elisa Molina</rdf:li>
               <rdf:li>Ferran Abancó</rdf:li>
               <rdf:li>Vicente Peg</rdf:li>
               <rdf:li>María Gión</rdf:li>
               <rdf:li>Laia Garrigós</rdf:li>
               <rdf:li>José Pérez-García</rdf:li>
               <rdf:li>Javier Cortés</rdf:li>
               <rdf:li>Mercè Martí</rdf:li>
            </rdf:Seq>
         </dc:creator>
         <dc:description>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Tumor-infiltrating lymphocytes (TILs) have predictive and prognostic value in breast cancer (BC) and exert a protective function against tumor growth, indicating that it is susceptible to treatment using adoptive cell transfer of TILs or T cell receptor (TCR)-based therapies.</rdf:li>
            </rdf:Alt>
         </dc:description>
         <dc:rights>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Copyright © 2023 Aran, Lázaro, Marco, Molina, Abancó, Peg, Gión, Garrigós, Pérez-García, Cortés and Martí. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</rdf:li>
            </rdf:Alt>
         </dc:rights>
         <dc:title>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Analysis of tumor infiltrating CD4+ and CD8+ CDR3 sequences reveals shared features putatively associated to the anti-tumor immune response</rdf:li>
            </rdf:Alt>
         </dc:title>
         <dc:subject>
            <rdf:Bag>
               <rdf:li>tumor-infiltrating lymphocytes</rdf:li>
               <rdf:li>CD4+ T cells</rdf:li>
               <rdf:li>CD8+ T cells</rdf:li>
               <rdf:li>T cell receptor</rdf:li>
               <rdf:li>breast cancer</rdf:li>
            </rdf:Bag>
         </dc:subject>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:pdf="http://ns.adobe.com/pdf/1.3/">
         <pdf:Keywords>tumor-infiltrating lymphocytes, CD4+ T cells, CD8+ T cells, T cell receptor, breast cancer</pdf:Keywords>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xmpRights="http://ns.adobe.com/xap/1.0/rights/">
         <xmpRights:Marked>True</xmpRights:Marked>
         <xmpRights:WebStatement>https://www.frontiersin.org/legal/copyright-statement</xmpRights:WebStatement>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xmp="http://ns.adobe.com/xap/1.0/">
         <xmp:ModifyDate>2023-08-01T15:52:07+08:00</xmp:ModifyDate>
         <xmp:CreateDate>2023-08-01T15:06:53+08:00</xmp:CreateDate>
         <xmp:MetadataDate>2023-08-01T15:52:07+08:00</xmp:MetadataDate>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xmpMM="http://ns.adobe.com/xap/1.0/mm/">
         <xmpMM:DocumentID>uuid:a1dd4cdc-f0d0-40fa-b1e9-ad4a20225f4f</xmpMM:DocumentID>
         <xmpMM:InstanceID>uuid:853b34c9-e795-4621-8f32-b15b5764dd41</xmpMM:InstanceID>
      </rdf:Description>
   </rdf:RDF>
</x:xmpmeta>
   Pages: 
    Page: 
     Label: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 222, 715, 502, 736
      Annotation: 
       Subtype: Link
       Rect: 222, 690, 447, 711
      Annotation: 
       Subtype: Link
       Rect: 222, 665, 469, 686
      Annotation: 
       Subtype: Link
       Rect: 222, 640, 535, 661
      Annotation: 
       Subtype: Link
       Rect: 222, 615, 545, 636
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
      Annotation: 
       Subtype: Link
       Rect: 49, 720, 125, 735
      Annotation: 
       Subtype: Link
       Rect: 60, 549, 127, 556
      Annotation: 
       Subtype: Link
       Rect: 49, 419, 158, 426
      Annotation: 
       Subtype: Link
       Rect: 155, 369, 180, 376
      Annotation: 
       Subtype: Link
       Rect: 49, 360, 168, 367
      Annotation: 
       Subtype: Link
       Rect: 454, 802, 510, 809
      Annotation: 
       Subtype: Link
       Rect: 471, 793, 521, 800
      Annotation: 
       Subtype: Link
       Rect: 451, 783, 543, 790
      Annotation: 
       Subtype: Link
       Rect: 49, 797, 233, 813
    Page: 
     Label: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 213, 690, 217, 699
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 221, 690, 225, 699
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 146, 590, 150, 599
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 155, 590, 159, 599
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 224, 528, 228, 537
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 158, 478, 163, 487
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 187, 353, 192, 362
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 196, 353, 205, 362
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 494, 606, 503, 615
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 369, 569, 378, 578
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 382, 569, 390, 578
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 349, 519, 358, 528
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 365, 519, 374, 528
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 304, 116, 387, 125
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 49, 744, 131, 753
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 255, 631, 285, 640
       Destination: 21
      Annotation: 
       Subtype: Link
       Rect: 236, 494, 290, 503
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 49, 481, 76, 490
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 364, 90, 371, 97
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 375, 90, 382, 97
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 103, 81, 111, 88
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 161, 81, 209, 88
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 132, 381, 140, 390
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 115, 369, 124, 378
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 153, 319, 162, 328
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 265, 219, 274, 228
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 278, 219, 287, 228
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 155, 156, 164, 165
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 169, 156, 178, 165
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 116, 144, 125, 153
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 465, 694, 473, 703
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 478, 694, 486, 703
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 532, 581, 540, 590
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 367, 569, 376, 578
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 438, 569, 446, 578
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 392, 244, 469, 253
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 491, 244, 545, 253
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 304, 232, 364, 241
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 405, 194, 495, 203
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 432, 144, 521, 153
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 97, 631, 181, 640
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 52, 594, 89, 603
       Destination: 85
      Annotation: 
       Subtype: Link
       Rect: 86, 531, 121, 540
       Destination: 85
      Annotation: 
       Subtype: Link
       Rect: 52, 494, 103, 503
       Destination: 85
      Annotation: 
       Subtype: Link
       Rect: 106, 456, 154, 465
       Destination: 85
      Annotation: 
       Subtype: Link
       Rect: 158, 456, 246, 465
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 188, 369, 222, 378
       Destination: 85
      Annotation: 
       Subtype: Link
       Rect: 112, 306, 147, 315
       Destination: 85
      Annotation: 
       Subtype: Link
       Rect: 94, 256, 203, 265
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 433, 644, 469, 653
       Destination: 102
      Annotation: 
       Subtype: Link
       Rect: 475, 581, 511, 590
       Destination: 102
      Annotation: 
       Subtype: Link
       Rect: 307, 556, 414, 565
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 396, 444, 447, 453
       Destination: 102
      Annotation: 
       Subtype: Link
       Rect: 307, 381, 344, 390
       Destination: 102
      Annotation: 
       Subtype: Link
       Rect: 308, 344, 411, 353
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 485, 319, 545, 328
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 304, 306, 341, 315
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 52, 78, 90, 87
       Destination: 130
      Annotation: 
       Subtype: Link
       Rect: 454, 90, 488, 99
       Destination: 130
      Annotation: 
       Subtype: Link
       Rect: 404, 161, 478, 169
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 493, 161, 497, 169
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 228, 152, 291, 159
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 128, 344, 234, 353
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 228, 294, 264, 303
       Destination: 130
      Annotation: 
       Subtype: Link
       Rect: 115, 182, 201, 191
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 49, 157, 96, 166
       Destination: 130
      Annotation: 
       Subtype: Link
       Rect: 93, 69, 201, 78
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 353, 319, 390, 328
       Destination: 130
      Annotation: 
       Subtype: Link
       Rect: 438, 182, 447, 191
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 454, 182, 463, 191
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 451, 144, 459, 153
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 466, 144, 475, 153
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 307, 94, 345, 103
       Destination: 150
      Annotation: 
       Subtype: Link
       Rect: 421, 69, 460, 78
       Destination: 150
      Annotation: 
       Subtype: Link
       Rect: 466, 69, 472, 78
       Destination: 150
      Annotation: 
       Subtype: Link
       Rect: 342, 403, 417, 410
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 433, 403, 437, 410
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 151, 394, 216, 401
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 197, 157, 232, 166
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 105, 132, 139, 141
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 195, 119, 232, 128
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 249, 107, 285, 116
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 361, 144, 449, 153
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 368, 225, 443, 232
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 459, 225, 463, 232
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 169, 216, 233, 223
       Destination: 251
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 9
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 219, 656, 228, 665
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 232, 656, 241, 665
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 267, 644, 276, 653
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 136, 606, 145, 615
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 99, 519, 125, 528
       Destination: 206
      Annotation: 
       Subtype: Link
       Rect: 148, 506, 157, 515
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 308, 694, 337, 703
       Destination: 206
      Annotation: 
       Subtype: Link
       Rect: 307, 681, 360, 690
       Destination: 189
      Annotation: 
       Subtype: Link
       Rect: 384, 656, 439, 665
       Destination: 189
      Annotation: 
       Subtype: Link
       Rect: 334, 581, 370, 590
       Destination: 189
      Annotation: 
       Subtype: Link
       Rect: 333, 556, 368, 565
       Destination: 189
      Annotation: 
       Subtype: Link
       Rect: 356, 519, 406, 528
       Destination: 189
      Annotation: 
       Subtype: Link
       Rect: 375, 117, 382, 124
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 386, 117, 393, 124
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 10
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 162, 265, 169, 272
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 173, 265, 180, 272
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 11
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 238, 206, 246, 215
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 371, 218, 380, 227
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 414, 193, 423, 202
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 400, 156, 408, 165
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 216, 441, 223, 448
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 12
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 277, 316, 285, 325
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 216, 253, 225, 262
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 260, 178, 269, 187
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 155, 91, 164, 100
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 168, 91, 177, 100
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 507, 428, 515, 437
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 475, 403, 483, 412
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 502, 328, 510, 337
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 469, 316, 477, 325
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 406, 291, 414, 300
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 420, 291, 429, 300
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 427, 278, 436, 287
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 13
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 52, 644, 61, 653
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 180, 544, 189, 553
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 242, 544, 250, 553
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 255, 544, 263, 553
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 253, 506, 262, 515
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 268, 506, 276, 515
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 178, 344, 187, 353
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 192, 344, 200, 353
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 241, 294, 250, 303
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 261, 294, 270, 303
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 276, 294, 285, 303
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 141, 231, 150, 240
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 431, 719, 440, 728
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 339, 606, 347, 615
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 468, 606, 476, 615
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 481, 606, 489, 615
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 504, 331, 512, 340
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 429, 169, 438, 178
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 521, 131, 530, 140
       Destination: 271
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 14
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 177, 606, 288, 615
      Annotation: 
       Subtype: Link
       Rect: 104, 594, 214, 603
      Annotation: 
       Subtype: Link
       Rect: 317, 269, 545, 278
      Annotation: 
       Subtype: Link
       Rect: 304, 256, 403, 265
      Annotation: 
       Subtype: Link
       Rect: 97, 174, 169, 181
      Annotation: 
       Subtype: Link
       Rect: 139, 155, 225, 162
      Annotation: 
       Subtype: Link
       Rect: 136, 128, 208, 135
      Annotation: 
       Subtype: Link
       Rect: 182, 101, 259, 108
      Annotation: 
       Subtype: Link
       Rect: 317, 174, 419, 181
      Annotation: 
       Subtype: Link
       Rect: 469, 155, 545, 162
      Annotation: 
       Subtype: Link
       Rect: 455, 128, 529, 135
      Annotation: 
       Subtype: Link
       Rect: 391, 101, 460, 108
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
    Page: 
     Label: 15
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 266, 758, 290, 765
      Annotation: 
       Subtype: Link
       Rect: 49, 750, 74, 757
      Annotation: 
       Subtype: Link
       Rect: 62, 715, 120, 722
      Annotation: 
       Subtype: Link
       Rect: 198, 688, 280, 695
      Annotation: 
       Subtype: Link
       Rect: 152, 661, 224, 668
      Annotation: 
       Subtype: Link
       Rect: 178, 634, 284, 641
      Annotation: 
       Subtype: Link
       Rect: 114, 599, 188, 606
      Annotation: 
       Subtype: Link
       Rect: 97, 572, 178, 579
      Annotation: 
       Subtype: Link
       Rect: 62, 537, 139, 544
      Annotation: 
       Subtype: Link
       Rect: 62, 510, 120, 517
      Annotation: 
       Subtype: Link
       Rect: 157, 483, 243, 490
      Annotation: 
       Subtype: Link
       Rect: 137, 456, 194, 463
      Annotation: 
       Subtype: Link
       Rect: 172, 429, 254, 436
      Annotation: 
       Subtype: Link
       Rect: 161, 410, 290, 417
      Annotation: 
       Subtype: Link
       Rect: 270, 391, 290, 398
      Annotation: 
       Subtype: Link
       Rect: 49, 383, 175, 390
      Annotation: 
       Subtype: Link
       Rect: 266, 364, 290, 371
      Annotation: 
       Subtype: Link
       Rect: 49, 356, 111, 363
      Annotation: 
       Subtype: Link
       Rect: 189, 321, 275, 328
      Annotation: 
       Subtype: Link
       Rect: 62, 294, 139, 301
      Annotation: 
       Subtype: Link
       Rect: 62, 267, 129, 274
      Annotation: 
       Subtype: Link
       Rect: 104, 240, 180, 247
      Annotation: 
       Subtype: Link
       Rect: 455, 742, 525, 749
      Annotation: 
       Subtype: Link
       Rect: 394, 715, 440, 722
      Annotation: 
       Subtype: Link
       Rect: 408, 688, 485, 695
      Annotation: 
       Subtype: Link
       Rect: 474, 669, 545, 676
      Annotation: 
       Subtype: Link
       Rect: 370, 642, 465, 649
      Annotation: 
       Subtype: Link
       Rect: 349, 615, 427, 622
      Annotation: 
       Subtype: Link
       Rect: 410, 588, 491, 595
      Annotation: 
       Subtype: Link
       Rect: 449, 561, 540, 568
      Annotation: 
       Subtype: Link
       Rect: 521, 534, 545, 541
      Annotation: 
       Subtype: Link
       Rect: 304, 526, 352, 533
      Annotation: 
       Subtype: Link
       Rect: 497, 499, 545, 506
      Annotation: 
       Subtype: Link
       Rect: 410, 472, 489, 479
      Annotation: 
       Subtype: Link
       Rect: 317, 437, 394, 444
      Annotation: 
       Subtype: Link
       Rect: 456, 410, 533, 417
      Annotation: 
       Subtype: Link
       Rect: 419, 383, 480, 390
      Annotation: 
       Subtype: Link
       Rect: 423, 364, 506, 371
      Annotation: 
       Subtype: Link
       Rect: 349, 345, 395, 352
      Annotation: 
       Subtype: Link
       Rect: 402, 326, 456, 333
      Annotation: 
       Subtype: Link
       Rect: 364, 298, 435, 305
      Annotation: 
       Subtype: Link
       Rect: 433, 269, 505, 276
      Annotation: 
       Subtype: Link
       Rect: 376, 240, 459, 247
      Annotation: 
       Subtype: Link
       Rect: 450, 799, 545, 806
      Annotation: 
       Subtype: Link
       Rect: 49, 33, 129, 40
      Annotation: 
       Subtype: Link
       Rect: 500, 33, 545, 40
  Checksum: 5569a9b7
   Type: CRC32
  Checksum: 3ab358e6d215e0c2af201f60053888cd
   Type: MD5
  Checksum: f7cb7db33e57ee060e4daa5a371b3881dafc95e2
   Type: SHA-1
  Checksum: ca164f51de33ff1bcc25e4d175a85cbe77aa3e46ccaf659d31952c83c634fe9d
   Type: SHA-256