c65f23b2a121bd536fb0c21620af0e09  pmc_10068420.pdf
8b3ac737d6c3f09da7f3695a3dd039d3e85ae497  pmc_10068420.pdf
b365661494141543cc29d4a044735e00a02d9b3d8e886286f78469723659a600  pmc_10068420.pdf

Title:          Increasing trend of antimicrobial resistance in Shigella associated with MSM transmission in Barcelona, 2020–21: outbreak of XRD Shigella sonnei and dissemination of ESBL-producing Shigella flexneri
Subject:        DOI: 10.1093/jac/dkad031; Journal of Antimicrobial Chemotherapy, 78, 4, 2023-02-10.; Abstract:  Background: Several countries have recently reported the detection of ESBL-producing Shigella sonnei associated with transmission among MSM. In a previous study by our group, 2.8% of Shigella spp. obtained from MSM in Barcelona between 2015 and 2019 were ESBL producers. Objectives: To describe and characterize the emerging ESBL-producing Shigella spp. associated with sexual transmission among MSM detected from 2020 to 2021 in Barcelona, elucidating their connectivity with contemporaneous ESBL-producing Shigella spp. from other countries. Results: From 2020 to 2021, we identified that among MSM, 68% of S. sonnei were XDR harbouring blaCTX-M-27 and 14% of Shigella flexneri were MDR harbouring blaCTX-M-27. WGS analysis showed that the ESBL-producing S. sonnei were part of a monophyletic cluster, which included isolates responsible for the prolonged outbreak occurring in the UK. Our data also reveal the first emergence and clonal dissemination of ESBL-producing and fluoroquinolone-resistant S. flexneri 2a among MSM. Conclusions: We report an increasing trend of antimicrobial resistance in Shigella spp. among MSM in Barcelona since 2021, mainly as a consequence of the dissemination of XDR ESBL-producing S. sonnei, previously reported in the UK. These results highlight the importance of international collaborative surveillance of MDR/XDR S. sonnei and S. flexneri for rapid identification of their emergence and the prevention of the transmission of these pathogens.
Keywords:       
Author:         Albert Moreno-Mingorance
Creator:        Servigistics Arbortext Advanced Print Publisher 11.1.4546/W-x64
Producer:       PDFlib+PDI 9.0.7p3 (C++/Win64)
CreationDate:   Tue Mar 21 09:13:24 2023 CET
ModDate:        Fri Mar 31 14:44:29 2023 CEST
Tagged:         yes
UserProperties: no
Suspects:       no
Form:           AcroForm
JavaScript:     no
Pages:          8
Encrypted:      no
Page size:      612.283 x 790.866 pts
Page rot:       0
File size:      590730 bytes
Optimized:      yes
PDF version:    1.6


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
VDKKGY+FSMe-LightItalic              Type 1C           Custom           yes yes yes    689  0
DNIKBK+FSMe-Light                    Type 1C           Custom           yes yes yes    692  0
ASQACJ+FSMe-Bold                     Type 1C           Custom           yes yes yes    695  0
AJULBE+FSMe-BoldItalic               Type 1C           Custom           yes yes yes    698  0
LTYWME+FSMe                          Type 1C           Custom           yes yes yes    701  0
PAZSAC+TimesNewRomanPSMT             CID TrueType      Identity-H       yes yes yes     91  0
YRJMQK+STIXGeneral-Regular           Type 1C           Custom           yes yes yes     95  0
EPBTHK+TimesNewRomanPSMT             Type 1            Custom           yes yes no      55  0
DFTAJR+ArialMT                       Type 1            Custom           yes yes no      58  0
OIXGJC+Arial-BoldMT                  Type 1            Custom           yes yes no      60  0
TUEQFP+ArialMT                       Type 1            Custom           yes yes no      63  0
LQWBNC+Arial-ItalicMT                Type 1            Custom           yes yes no      64  0
BVFZBA+FSMe-Light                    Type 1            Custom           yes yes no      66  0
FGKFCD+ArialMT                       Type 1            Custom           yes yes no      70  0
BWHXOJ+Arial-BoldMT                  Type 1            Custom           yes yes no      73  0
LQWBNC+Arial-ItalicMT                Type 1            Custom           yes yes no      74  0


Jhove (Rel. 1.22.1, 2019-04-17)
 Date: 2023-08-02 02:26:03 CEST
 RepresentationInformation: pmc_10068420.pdf
  ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17)
  LastModified: 2023-08-01 02:38:38 CEST
  Size: 590730
  Format: PDF
  Version: 1.6
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  Profile: Linearized PDF, Tagged PDF
  PDFMetadata: 
   Objects: 0
   FreeObjects: 1
   IncrementalUpdates: 0
   DocumentCatalog: 
    ViewerPreferences: 
     HideToolbar: false
     HideMenubar: false
     HideWindowUI: false
     FitWindow: false
     CenterWindow: false
     DisplayDocTitle: true
     NonFullScreenPageMode: UseNone
     Direction: L2R
     ViewArea: CropBox
     ViewClip: CropBox
     PrintArea: CropBox
     PageClip: CropBox
    PageLayout: OneColumn
    PageMode: UseOutlines
    Language: en
    Outlines: 
     Item: 
      Title: Increasing trend of antimicrobial resistance in Shigella associated
with MSM transmission in Barcelona, 2020 21: outbreak of XRD Shigella
sonnei and dissemination of ESBL-producing Shigella flexneri
      Children: 
       Item: 
        Title: Introduction
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1
       Item: 
        Title: Methods
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4a87761d
        Children: 
         Item: 
          Title: Study population and bacterial isolates
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89
         Item: 
          Title: Antibiotic susceptibility testing (AST)
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9
         Item: 
          Title: WGS and bioinformatic analysis
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e
         Item: 
          Title: Data analysis
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4671e53b
         Item: 
          Title: Sequence data deposition
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@2db7a79b
         Item: 
          Title: Ethics
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6950e31
       Item: 
        Title: Results
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@b7dd107
        Children: 
         Item: 
          Title: Bacterial isolates and antimicrobial resistance
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@42eca56e
         Item: 
          Title: Genomic analysis of blaCTX-M-27-encoding plasmids
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@52f759d7
         Item: 
          Title: Genotyping, serotyping and genomic epidemiology of Shigella spp.
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7cbd213e
       Item: 
        Title: Discussion
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@192d3247
       Item: 
        Title: Acknowledgements
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3ecd23d9
       Item: 
        Title: Funding
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@569cfc36
       Item: 
        Title: Transparency declarations
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@43bd930a
       Item: 
        Title: Supplementary data
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@33723e30
       Item: 
        Title: References
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@64f6106c
   Filters: 
    FilterPipeline: FlateDecode
   Fonts: 
    Type0: 
     Font: 
      BaseFont: PAZSAC+TimesNewRomanPSMT
      Encoding: Identity-H
      ToUnicode: true
    Type1: 
     Font: 
      BaseFont: VDKKGY+FSMe-LightItalic
      FontSubset: true
      FirstChar: 1
      LastChar: 68
      FontDescriptor: 
       FontName: VDKKGY+FSMe-LightItalic
       Flags: Nonsymbolic, Italic
       FontBBox: -148, -276, 1184, 1034
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: DNIKBK+FSMe-Light
      FontSubset: true
      FirstChar: 1
      LastChar: 85
      FontDescriptor: 
       FontName: DNIKBK+FSMe-Light
       Flags: Nonsymbolic
       FontBBox: -82, -276, 1220, 1033
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: ASQACJ+FSMe-Bold
      FontSubset: true
      FirstChar: 1
      LastChar: 71
      FontDescriptor: 
       FontName: ASQACJ+FSMe-Bold
       Flags: Nonsymbolic, ForceBold
       FontBBox: -80, -318, 1312, 1128
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: AJULBE+FSMe-BoldItalic
      FontSubset: true
      FirstChar: 1
      LastChar: 41
      FontDescriptor: 
       FontName: AJULBE+FSMe-BoldItalic
       Flags: Nonsymbolic, Italic, ForceBold
       FontBBox: -151, -319, 1274, 1133
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: LTYWME+FSMe
      FontSubset: true
      FirstChar: 1
      LastChar: 4
      FontDescriptor: 
       FontName: LTYWME+FSMe
       Flags: Nonsymbolic
       FontBBox: -84, -300, 1231, 1040
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: YRJMQK+STIXGeneral-Regular
      FontSubset: true
      FirstChar: 1
      LastChar: 6
      FontDescriptor: 
       FontName: YRJMQK+STIXGeneral-Regular
       Flags: Nonsymbolic
       FontBBox: -995, -455, 2000, 1055
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
    CIDFontType2: 
     Font: 
      BaseFont: PAZSAC+TimesNewRomanPSMT
      CIDSystemInfo: 
       Registry: Adobe
       Registry: Identity
       Supplement: 0
      FontDescriptor: 
       FontName: PAZSAC+TimesNewRomanPSMT
       Flags: Nonsymbolic
       FontBBox: -568, -307, 2046, 1040
       FontFile2: true
   XMP: <x:xmpmeta xmlns:x="adobe:ns:meta/" x:xmptk="Adobe XMP Core 5.4-c006 80.159825, 2016/09/16-03:31:08        ">
   <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about=""
            xmlns:xmpMM="http://ns.adobe.com/xap/1.0/mm/"
            xmlns:xmpRights="http://ns.adobe.com/xap/1.0/rights/"
            xmlns:pdf="http://ns.adobe.com/pdf/1.3/"
            xmlns:dc="http://purl.org/dc/elements/1.1/"
            xmlns:prism="http://prismstandard.org/namespaces/basic/2.0/"
            xmlns:xmp="http://ns.adobe.com/xap/1.0/"
            xmlns:pdfx="http://ns.adobe.com/pdfx/1.3/"
            xmlns:pdfuaid="http://www.aiim.org/pdfua/ns/id/"
            xmlns:pdfaExtension="http://www.aiim.org/pdfa/ns/extension/"
            xmlns:pdfaSchema="http://www.aiim.org/pdfa/ns/schema#"
            xmlns:pdfaProperty="http://www.aiim.org/pdfa/ns/property#">
         <xmpMM:InstanceID>uuid:38c1a679-65db-472a-943c-51a870401c5d</xmpMM:InstanceID>
         <xmpMM:DocumentID>uuid:6F2B90D8-6FA6-81D7-6007-511865049E47</xmpMM:DocumentID>
         <xmpRights:Marked>True</xmpRights:Marked>
         <pdf:Producer>PDFlib+PDI 9.0.7p3 (C++/Win64)</pdf:Producer>
         <pdf:Keywords/>
         <dc:format>application/pdf</dc:format>
         <dc:identifier>10.1093/jac/dkad031</dc:identifier>
         <dc:lang>en</dc:lang>
         <dc:publisher>
            <rdf:Bag>
               <rdf:li>Oxford University Press</rdf:li>
            </rdf:Bag>
         </dc:publisher>
         <dc:title>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Increasing trend of antimicrobial resistance in Shigella associated with MSM transmission in Barcelona, 2020–21: outbreak of XRD Shigella sonnei and dissemination of ESBL-producing Shigella flexneri</rdf:li>
            </rdf:Alt>
         </dc:title>
         <dc:creator>
            <rdf:Seq>
               <rdf:li>Albert Moreno-Mingorance</rdf:li>
               <rdf:li>Alba Mir-Cros</rdf:li>
               <rdf:li>Lidia Goterris</rdf:li>
               <rdf:li>Virginia Rodriguez-Garrido</rdf:li>
               <rdf:li>Elena Sulleiro</rdf:li>
               <rdf:li>M. Jesús Barberà</rdf:li>
               <rdf:li>Mireia Alberny</rdf:li>
               <rdf:li>Yannick Hoyos-Mallecot</rdf:li>
               <rdf:li>Vicente Descalzo</rdf:li>
               <rdf:li>Albert Bravo</rdf:li>
               <rdf:li>Josep Roca-Grande</rdf:li>
               <rdf:li>Belén Viñado</rdf:li>
               <rdf:li>Tomàs Pumarola</rdf:li>
               <rdf:li>M. Nieves Larrosa</rdf:li>
               <rdf:li>Juan José González-López</rdf:li>
            </rdf:Seq>
         </dc:creator>
         <dc:description>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">DOI: 10.1093/jac/dkad031; Journal of Antimicrobial Chemotherapy, 78, 4, 2023-02-10.; Abstract:  Background: Several countries have recently reported the detection of ESBL-producing Shigella sonnei associated with transmission among MSM. In a previous study by our group, 2.8% of Shigella spp. obtained from MSM in Barcelona between 2015 and 2019 were ESBL producers. Objectives: To describe and characterize the emerging ESBL-producing Shigella spp. associated with sexual transmission among MSM detected from 2020 to 2021 in Barcelona, elucidating their connectivity with contemporaneous ESBL-producing Shigella spp. from other countries. Results: From 2020 to 2021, we identified that among MSM, 68% of S. sonnei were XDR harbouring blaCTX-M-27 and 14% of Shigella flexneri were MDR harbouring blaCTX-M-27. WGS analysis showed that the ESBL-producing S. sonnei were part of a monophyletic cluster, which included isolates responsible for the prolonged outbreak occurring in the UK. Our data also reveal the first emergence and clonal dissemination of ESBL-producing and fluoroquinolone-resistant S. flexneri 2a among MSM. Conclusions: We report an increasing trend of antimicrobial resistance in Shigella spp. among MSM in Barcelona since 2021, mainly as a consequence of the dissemination of XDR ESBL-producing S. sonnei, previously reported in the UK. These results highlight the importance of international collaborative surveillance of MDR/XDR S. sonnei and S. flexneri for rapid identification of their emergence and the prevention of the transmission of these pathogens.</rdf:li>
            </rdf:Alt>
         </dc:description>
         <dc:rights>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.</rdf:li>
            </rdf:Alt>
         </dc:rights>
         <prism:aggregationType>Journal</prism:aggregationType>
         <prism:publicationName>Journal of Antimicrobial Chemotherapy</prism:publicationName>
         <prism:copyright>© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.</prism:copyright>
         <prism:issn>0305-7453</prism:issn>
         <prism:elssn>1460-2091</prism:elssn>
         <prism:volume>78</prism:volume>
         <prism:number>4</prism:number>
         <prism:issueName/>
         <prism:startingPage>975</prism:startingPage>
         <prism:endingPage>982</prism:endingPage>
         <prism:doi>10.1093/jac/dkad031</prism:doi>
         <prism:url>https://doi.org/10.1093/jac/dkad031</prism:url>
         <xmp:CreateDate>2023-03-21T13:43:24+05:30</xmp:CreateDate>
         <xmp:ModifyDate>2023-03-31T18:14:29+05:30</xmp:ModifyDate>
         <xmp:CreatorTool>Servigistics Arbortext Advanced Print Publisher 11.1.4546/W-x64</xmp:CreatorTool>
         <xmp:MetadataDate>2023-03-31T18:14:29+05:30</xmp:MetadataDate>
         <pdfx:EPSprocessor>PStill version 1.84.42</pdfx:EPSprocessor>
         <pdfuaid:part>1</pdfuaid:part>
         <pdfaExtension:schemas>
            <rdf:Bag>
               <rdf:li rdf:parseType="Resource">
                  <pdfaSchema:schema>PDF/UA Universal Accessibility Schema</pdfaSchema:schema>
                  <pdfaSchema:namespaceURI>http://www.aiim.org/pdfua/ns/id/</pdfaSchema:namespaceURI>
                  <pdfaSchema:prefix>pdfuaid</pdfaSchema:prefix>
                  <pdfaSchema:property>
                     <rdf:Seq>
                        <rdf:li rdf:parseType="Resource">
                           <pdfaProperty:name>part</pdfaProperty:name>
                           <pdfaProperty:valueType>Integer</pdfaProperty:valueType>
                           <pdfaProperty:category>internal</pdfaProperty:category>
                           <pdfaProperty:description>Indicates, which part of ISO 14289 standard is followed</pdfaProperty:description>
                        </rdf:li>
                     </rdf:Seq>
                  </pdfaSchema:property>
               </rdf:li>
            </rdf:Bag>
         </pdfaExtension:schemas>
      </rdf:Description>
   </rdf:RDF>
</x:xmpmeta>
   Pages: 
    Page: 
     Sequence: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 355, 555, 365, 565
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 305, 467, 418, 475
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 288, 142, 299, 151
       Flags: Print
       Destination: 26
      Annotation: 
       Subtype: Link
       Rect: 442, 197, 446, 206
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 448, 197, 452, 206
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 433, 152, 436, 161
       Flags: Print
       Destination: 26
      Annotation: 
       Subtype: Link
       Rect: 438, 152, 453, 161
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 348, 108, 356, 117
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 495, 61, 522, 69
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 50, 195, 58
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 712, 203, 722
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 445, 711, 569, 766
       Flags: Print
    Page: 
     Sequence: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 85, 666, 93, 675
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 230, 397, 295, 405
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 90, 370, 96, 378
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 133, 170, 140, 178
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 142, 170, 149, 178
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 455, 669, 462, 677
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 463, 669, 470, 677
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 547, 596, 569, 604
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 586, 353, 594
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 536, 556, 545, 564
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 339, 546, 412, 554
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 385, 123, 391, 132
       Flags: Print
       Destination: 4
      Annotation: 
       Subtype: Link
       Rect: 423, 79, 428, 88
       Flags: Print
       Destination: 4
    Page: 
     Sequence: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 105, 319, 110, 328
       Flags: Print
       Destination: 7
      Annotation: 
       Subtype: Link
       Rect: 176, 242, 185, 251
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 552, 323, 560, 332
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 561, 323, 569, 332
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 545, 198, 550, 207
       Flags: Print
       Destination: 7
      Annotation: 
       Subtype: Link
       Rect: 337, 187, 347, 196
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 457, 101, 472, 110
       Flags: Print
       Destination: 12
      Annotation: 
       Subtype: Link
       Rect: 477, 105, 485, 114
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 487, 68, 503, 77
       Flags: Print
       Destination: 12
    Page: 
     Sequence: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 154, 431, 159, 440
       Flags: Print
       Destination: 12
      Annotation: 
       Subtype: Link
       Rect: 167, 310, 183, 319
       Flags: Print
       Destination: 12
      Annotation: 
       Subtype: Link
       Rect: 188, 314, 192, 323
       Flags: Print
       Destination: 26
      Annotation: 
       Subtype: Link
       Rect: 193, 314, 201, 323
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 114, 244, 130, 253
       Flags: Print
       Destination: 12
      Annotation: 
       Subtype: Link
       Rect: 71, 123, 76, 132
       Flags: Print
       Destination: 20
      Annotation: 
       Subtype: Link
       Rect: 71, 57, 76, 66
       Flags: Print
       Destination: 20
      Annotation: 
       Subtype: Link
       Rect: 82, 61, 89, 70
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 91, 61, 99, 70
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 397, 350, 405, 359
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 418, 295, 422, 304
       Flags: Print
       Destination: 26
      Annotation: 
       Subtype: Link
       Rect: 487, 250, 491, 259
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 493, 250, 501, 259
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 502, 250, 510, 259
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 399, 217, 403, 226
       Flags: Print
       Destination: 26
      Annotation: 
       Subtype: Link
       Rect: 404, 217, 412, 226
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 494, 194, 501, 203
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 356, 161, 364, 170
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 555, 105, 559, 114
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 561, 105, 569, 114
       Flags: Print
       Destination: 29
    Page: 
     Sequence: 5
    Page: 
     Sequence: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 529, 61, 537, 70
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 538, 61, 546, 70
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 548, 61, 556, 70
       Flags: Print
       Destination: 29
    Page: 
     Sequence: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 62, 611, 70, 620
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 115, 501, 123, 510
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 86, 204, 94, 213
       Flags: Print
       Destination: 29
      Annotation: 
       Subtype: Link
       Rect: 334, 205, 343, 213
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 380, 205, 389, 213
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 446, 205, 519, 213
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 155, 316, 163
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 544, 135, 569, 143
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 125, 422, 133
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 111, 316, 119
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 544, 91, 569, 99
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 81, 447, 89
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 67, 316, 75
       Flags: Print
       Destination: 649
    Page: 
     Sequence: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 42, 686, 217, 694
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 674, 46, 682
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 146, 644, 274, 652
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 632, 46, 640
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 42, 602, 191, 610
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 590, 46, 598
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 109, 570, 228, 578
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 558, 46, 566
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 156, 538, 299, 546
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 528, 74, 536
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 516, 46, 524
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 236, 496, 299, 504
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 486, 99, 494
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 474, 46, 482
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 163, 444, 299, 452
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 432, 51, 440
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 126, 412, 299, 420
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 402, 296, 410
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 390, 51, 398
       Flags: Print
       Destination: 649
      Annotation: 
       Subtype: Link
       Rect: 42, 360, 215, 368
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 348, 51, 356
       Flags: Print
       Destination: 1
      Annotation: 
       Subtype: Link
       Rect: 211, 318, 299, 326
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 42, 308, 131, 316
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 696, 320, 704
       Flags: Print
       Destination: 1
      Annotation: 
       Subtype: Link
       Rect: 459, 666, 569, 674
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 656, 380, 664
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 642, 320, 650
       Flags: Print
       Destination: 1
      Annotation: 
       Subtype: Link
       Rect: 311, 612, 454, 620
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 599, 320, 607
       Flags: Print
       Destination: 1
      Annotation: 
       Subtype: Link
       Rect: 427, 579, 568, 587
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 565, 320, 573
       Flags: Print
       Destination: 4
      Annotation: 
       Subtype: Link
       Rect: 531, 545, 569, 553
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 535, 434, 543
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 522, 320, 530
       Flags: Print
       Destination: 7
      Annotation: 
       Subtype: Link
       Rect: 471, 502, 569, 510
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 492, 334, 500
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 478, 320, 486
       Flags: Print
       Destination: 7
      Annotation: 
       Subtype: Link
       Rect: 516, 458, 569, 466
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 448, 396, 456
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 435, 320, 443
       Flags: Print
       Destination: 7
      Annotation: 
       Subtype: Link
       Rect: 531, 405, 569, 413
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 395, 428, 403
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 381, 320, 389
       Flags: Print
       Destination: 20
      Annotation: 
       Subtype: Link
       Rect: 446, 351, 569, 359
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 341, 363, 349
       Flags: Print
      Annotation: 
       Subtype: Link
       Rect: 311, 328, 320, 336
       Flags: Print
       Destination: 26
      Annotation: 
       Subtype: Link
       Rect: 342, 308, 504, 316
       Flags: Print
  Checksum: 59a1cdc9
   Type: CRC32
  Checksum: c65f23b2a121bd536fb0c21620af0e09
   Type: MD5
  Checksum: 8b3ac737d6c3f09da7f3695a3dd039d3e85ae497
   Type: SHA-1