fcba9972bba5662fd6340a0339eacd74  PIIS1465324923010393.pdf
29f1cd3dedb2d6d43831ac778239f2c9fd04dd99  PIIS1465324923010393.pdf
dcbd0a0aef89b410508c1ecd04f895b77f6b1a8d5516f3984c8d88319e40682b  PIIS1465324923010393.pdf

Title:           Comparability exercise of critical quality attributes of clinical-grade human mesenchymal stromal cells from the Wharton’s jelly: single-use stirred tank bioreactors versus planar culture systems
Subject:         Cytotherapy, 26 (2024) 418-426. doi:10.1016/j.jcyt.2023.08.008
Keywords:        "advanced therapy medicinal product"; "bioprocessing"; "comparability exercise"; "Good Manufacturing Practice"; "microcarriers"; "single-use stirred tank bioreactor"; "umbilical cord mesenchymal stromal cell"
Author:          Alba López-Fernández
Creator:         Elsevier
Producer:        Acrobat Distiller 10.0.0 (Windows)
CreationDate:    Mon Apr 22 08:23:54 2024 CEST
ModDate:         Mon Apr 22 08:24:23 2024 CEST
Custom Metadata: yes
Metadata Stream: yes
Tagged:          yes
UserProperties:  no
Suspects:        no
Form:            none
JavaScript:      no
Pages:           9
Encrypted:       no
Page size:       595.276 x 793.701 pts
Page rot:        0
File size:       1755869 bytes
Optimized:       yes
PDF version:     1.7


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
LKNEEC+AdvTTb83ee1dd.B               Type 1C           WinAnsi          yes yes no     585  0
LKNEDO+AdvOTf2586c63+20              Type 1C           WinAnsi          yes yes no     588  0
LKNECM+AdvTT5843c571                 Type 1C           WinAnsi          yes yes no     591  0
LKNECK+AdvOTf2586c63                 Type 1C           WinAnsi          yes yes no     594  0
LKNEEB+AdvP4C9542                    Type 1C           WinAnsi          yes yes no     597  0
LKNEMA+AdvP3D0CBF                    Type 1C           WinAnsi          yes yes no     600  0
LKNECL+AdvP4C9543                    Type 1C           Custom           yes yes yes    603  0
LKMNCF+AdvOT5fa4e291                 Type 1C           WinAnsi          yes yes no     608  0
LKNECJ+AdvP4C4E59                    Type 1C           Custom           yes yes yes    611  0
LKNEDN+AdvOTf2586c63+fb              Type 1C           Custom           yes yes yes    616  0
LKNEEA+AdvOT5fa4e291+fb              Type 1C           Custom           yes yes yes    621  0
LKNEDP+AdvP4C4E74                    Type 1C           Custom           yes yes no     626  0
LKNELP+AdvPAC3D                      Type 1C           WinAnsi          yes yes no     630  0
LKNECI+AdvOT5fa4e291+20              Type 1C           WinAnsi          yes yes no     633  0
LKNFLL+AdvP4A5FDB                    Type 1C           WinAnsi          yes yes no     239  0
LKONDC+AdvTT488bbd95+08              Type 1C           Custom           yes yes yes     86  0
LKONDD+AdvPi2                        Type 1C           WinAnsi          yes yes no      91  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2024-06-15 02:41:34 CEST
 RepresentationInformation: PIIS1465324923010393.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2024-06-14 18:54:07 CEST
  Size: 1755869
  Format: PDF
  Version: 1.7
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  Profile: Linearized PDF, Tagged PDF
  PDFMetadata: 
   Objects: 725
   FreeObjects: 1
   IncrementalUpdates: 1
   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: SinglePage
    PageMode: UseOutlines
    Outlines: 
     Item: 
      Title: Comparability exercise of critical quality attributes of clinical-grade human mesenchymal stromal cells from the Wharton´s jelly: single-use stirred tank bioreactors versus planar culture systems
      Destination: Head1
      Children: 
       Item: 
        Title: Introduction
        Destination: Head2
       Item: 
        Title: Methods
        Destination: Head3
        Children: 
         Item: 
          Title: MSC,WJ initial cell culture and intermediate product production
          Destination: Head4
         Item: 
          Title: MSC,WJ large-scale expansion in 2D cultures using planar surfaces
          Destination: Head5
         Item: 
          Title: MSC,WJ large-scale expansion in 3D cultures using microcarriers and 3-L single-use STR
          Destination: Head6
         Item: 
          Title: Cell counting and viability analyses
          Destination: Head7
         Item: 
          Title: Immunophenotype analysis
          Destination: Head8
         Item: 
          Title: Live/Dead assays
          Destination: Head9
         Item: 
          Title: Metabolite analysis
          Destination: Head10
         Item: 
          Title: Microbiological, endotoxin adventitious virus testing and Mycoplasma detection
          Destination: Head11
         Item: 
          Title: Immunomodulation assay
          Destination: Head12
         Item: 
          Title: Differentiation assays
          Destination: Head13
         Item: 
          Title: hTERT activity
          Destination: Head14
         Item: 
          Title: Senescence assay
          Destination: Head15
         Item: 
          Title: Karyotype
          Destination: Head16
         Item: 
          Title: Cumulative Population Doublings
          Destination: Head17
         Item: 
          Title: Data analysis
          Destination: Head18
       Item: 
        Title: Results
        Destination: Head19
        Children: 
         Item: 
          Title: MSC,WJ scale-up in a 3-L single-use STR
          Destination: Head20
         Item: 
          Title: CQA assessment and comparability exercise
          Destination: Head21
       Item: 
        Title: Discussion
        Destination: Head22
        Children: 
         Item: 
          Title: Conclusions
          Destination: Head23
       Item: 
        Title: Author Contributions
        Destination: Head24
       Item: 
        Title: Declaration of Competing Interest
        Destination: Head25
       Item: 
        Title: Acknowledgments
        Destination: Head26
       Item: 
        Title: References
        Destination: Head27
   Info: 
    Title: Comparability exercise of critical quality attributes of clinical-grade human mesenchymal stromal cells from the Wharton’s jelly: single-use stirred tank bioreactors versus planar culture systems
    Author: Alba López-Fernández
    Subject: Cytotherapy, 26 (2024) 418-426. doi:10.1016/j.jcyt.2023.08.008
    Keywords: "advanced therapy medicinal product"; "bioprocessing"; "comparability exercise"; "Good Manufacturing Practice"; "microcarriers"; "single-use stirred tank bioreactor"; "umbilical cord mesenchymal stromal cell"
    Creator: Elsevier
    Producer: Acrobat Distiller 10.0.0 (Windows)
    CreationDate: Mon Apr 22 08:53:54 CEST 2024
    ModDate: Mon Apr 22 08:54:23 CEST 2024
   ID: 0x27f22a484eec5b4b6964ca04bcde2ba0, 0xf5381b9acb4e0229601ea8826bf7a688
   Filters: 
    FilterPipeline: FlateDecode
    FilterPipeline: DCTDecode
   Images: 
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1785
      ImageHeight: 1259
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 856
      ImageHeight: 547
      ColorSpace: black is zero
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1771
      ImageHeight: 841
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1786
      ImageHeight: 2040
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
   Fonts: 
    Type1: 
     Font: 
      BaseFont: LKMNCF+AdvOT5fa4e291
      FontSubset: true
      FirstChar: 37
      LastChar: 237
      FontDescriptor: 
       FontName: LKMNCF+AdvOT5fa4e291
       Flags: Serif, Nonsymbolic
       FontBBox: -72, -250, 1041, 979
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNECJ+AdvP4C4E59
      FontSubset: true
      FirstChar: 1
      LastChar: 126
      FontDescriptor: 
       FontName: LKNECJ+AdvP4C4E59
       Flags: Symbolic
       FontBBox: -31, -250, 1000, 750
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: LKNEDN+AdvOTf2586c63+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: LKNEDN+AdvOTf2586c63+fb
       Flags: Symbolic
       FontBBox: -114, -208, 833, 781
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: LKNEEC+AdvTTb83ee1dd.B
      FontSubset: true
      FirstChar: 46
      LastChar: 119
      FontDescriptor: 
       FontName: LKNEEC+AdvTTb83ee1dd.B
       Flags: Nonsymbolic
       FontBBox: -93, -250, 1041, 989
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNEDO+AdvOTf2586c63+20
      FontSubset: true
      FirstChar: 146
      LastChar: 146
      FontDescriptor: 
       FontName: LKNEDO+AdvOTf2586c63+20
       Flags: Nonsymbolic
       FontBBox: -41, -208, 885, 781
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNEEA+AdvOT5fa4e291+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: LKNEEA+AdvOT5fa4e291+fb
       Flags: Symbolic
       FontBBox: 40, 0, 572, 781
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: LKNECM+AdvTT5843c571
      FontSubset: true
      FirstChar: 184
      LastChar: 184
      FontDescriptor: 
       FontName: LKNECM+AdvTT5843c571
       Flags: Nonsymbolic
       FontBBox: -72, -208, 927, 875
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNFLL+AdvP4A5FDB
      FontSubset: true
      FirstChar: 98
      LastChar: 109
      FontDescriptor: 
       FontName: LKNFLL+AdvP4A5FDB
       Flags: Nonsymbolic
       FontBBox: 0, -239, 979, 718
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNECK+AdvOTf2586c63
      FontSubset: true
      FirstChar: 40
      LastChar: 122
      FontDescriptor: 
       FontName: LKNECK+AdvOTf2586c63
       Flags: Serif, Nonsymbolic
       FontBBox: -135, -229, 1052, 968
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNEDP+AdvP4C4E74
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: LKNEDP+AdvP4C4E74
       Flags: Symbolic
       FontBBox: -20, -958, 1114, 770
       FontFile3: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: LKNEEB+AdvP4C9542
      FontSubset: true
      FirstChar: 60
      LastChar: 62
      FontDescriptor: 
       FontName: LKNEEB+AdvP4C9542
       Flags: Nonsymbolic
       FontBBox: 0, -208, 979, 677
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNELP+AdvPAC3D
      FontSubset: true
      FirstChar: 45
      LastChar: 121
      FontDescriptor: 
       FontName: LKNELP+AdvPAC3D
       Flags: Nonsymbolic
       FontBBox: -166, -239, 989, 791
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKONDC+AdvTT488bbd95+08
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: LKONDC+AdvTT488bbd95+08
       Flags: Symbolic
       FontBBox: 82, 0, 562, 656
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: LKNEMA+AdvP3D0CBF
      FontSubset: true
      FirstChar: 65
      LastChar: 89
      FontDescriptor: 
       FontName: LKNEMA+AdvP3D0CBF
       Flags: Nonsymbolic
       FontBBox: -135, -260, 1197, 739
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNECI+AdvOT5fa4e291+20
      FontSubset: true
      FirstChar: 146
      LastChar: 150
      FontDescriptor: 
       FontName: LKNECI+AdvOT5fa4e291+20
       Flags: Nonsymbolic
       FontBBox: 19, -208, 947, 781
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: LKNECL+AdvP4C9543
      FontSubset: true
      FirstChar: 2
      LastChar: 167
      FontDescriptor: 
       FontName: LKNECL+AdvP4C9543
       Flags: Symbolic
       FontBBox: 0, -947, 1041, 895
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: LKONDD+AdvPi2
      FontSubset: true
      FirstChar: 101
      LastChar: 101
      FontDescriptor: 
       FontName: LKONDD+AdvPi2
       Flags: Nonsymbolic
       FontBBox: 16, -335, 981, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
   XMP: <x:xmpmeta xmlns:x="adobe:ns:meta/" x:xmptk="XMP Core 5.1.2">
   <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about=""
            xmlns:xmp="http://ns.adobe.com/xap/1.0/">
         <xmp:CreateDate>2024-04-22T11:53:54+05:30</xmp:CreateDate>
         <xmp:CreatorTool>Elsevier</xmp:CreatorTool>
         <xmp:ModifyDate>2024-04-22T11:54:23+05:30</xmp:ModifyDate>
         <xmp:MetadataDate>2024-04-22T11:54:23+05:30</xmp:MetadataDate>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:pdf="http://ns.adobe.com/pdf/1.3/">
         <pdf:Producer>Acrobat Distiller 10.0.0 (Windows)</pdf:Producer>
         <pdf:Keywords>"advanced therapy medicinal product"; "bioprocessing"; "comparability exercise"; "Good Manufacturing Practice"; "microcarriers"; "single-use stirred tank bioreactor"; "umbilical cord mesenchymal stromal cell"</pdf:Keywords>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:tdm="http://www.w3.org/ns/tdmrep/">
         <tdm:reservation>1</tdm:reservation>
         <tdm:policy>https://www.elsevier.com/tdm/tdmrep-policy.json</tdm:policy>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:dc="http://purl.org/dc/elements/1.1/">
         <dc:format>application/pdf</dc:format>
         <dc:identifier>doi:10.1016/j.jcyt.2023.08.008</dc:identifier>
         <dc:publisher>
            <rdf:Bag>
               <rdf:li>Elsevier Inc.</rdf:li>
            </rdf:Bag>
         </dc:publisher>
         <dc:description>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Cytotherapy, 26 (2024) 418-426. doi:10.1016/j.jcyt.2023.08.008</rdf:li>
            </rdf:Alt>
         </dc:description>
         <dc:subject>
            <rdf:Bag>
               <rdf:li>advanced therapy medicinal product</rdf:li>
               <rdf:li>bioprocessing</rdf:li>
               <rdf:li>comparability exercise</rdf:li>
               <rdf:li>Good Manufacturing Practice</rdf:li>
               <rdf:li>microcarriers</rdf:li>
               <rdf:li>single-use stirred tank bioreactor</rdf:li>
               <rdf:li>umbilical cord mesenchymal stromal cell</rdf:li>
            </rdf:Bag>
         </dc:subject>
         <dc:title>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Comparability exercise of critical quality attributes of clinical-grade human mesenchymal stromal cells from the Wharton’s jelly: single-use stirred tank bioreactors versus planar culture systems</rdf:li>
            </rdf:Alt>
         </dc:title>
         <dc:creator>
            <rdf:Seq>
               <rdf:li>Alba López-Fernández</rdf:li>
               <rdf:li>Margarita Codinach</rdf:li>
               <rdf:li>Maria Isabel Coca</rdf:li>
               <rdf:li>Cristina Prat-Vidal</rdf:li>
               <rdf:li>Julio Castaño</rdf:li>
               <rdf:li>Sílvia Torrents</rdf:li>
               <rdf:li>Gemma Aran</rdf:li>
               <rdf:li>Luciano Rodríguez</rdf:li>
               <rdf:li>Sergi Querol</rdf:li>
               <rdf:li>Joaquim Vives</rdf:li>
            </rdf:Seq>
         </dc:creator>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xmpMM="http://ns.adobe.com/xap/1.0/mm/">
         <xmpMM:DocumentID>uuid:fd8cfc10-4791-4a8b-8025-00abb91efa0c</xmpMM:DocumentID>
         <xmpMM:InstanceID>uuid:804f7085-e78c-4163-81bb-8f520f0b35f7</xmpMM:InstanceID>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:prism_1_="http://prismstandard.org/namespaces/basic/3.0/">
         <prism_1_:aggregationType>journal</prism_1_:aggregationType>
         <prism_1_:copyright>© 2023 International Society for Cell &amp; Gene Therapy. Published by Elsevier Inc.</prism_1_:copyright>
         <prism_1_:publicationName>Cytotherapy</prism_1_:publicationName>
         <prism_1_:issn>1465-3249</prism_1_:issn>
         <prism_1_:volume>26</prism_1_:volume>
         <prism_1_:number>5</prism_1_:number>
         <prism_1_:doi>10.1016/j.jcyt.2023.08.008</prism_1_:doi>
         <prism_1_:url>https://doi.org/10.1016/j.jcyt.2023.08.008</prism_1_:url>
         <prism_1_:startingPage>418</prism_1_:startingPage>
         <prism_1_:endingPage>426</prism_1_:endingPage>
         <prism_1_:pageRange>418-426</prism_1_:pageRange>
         <prism_1_:coverDisplayDate>May 2024</prism_1_:coverDisplayDate>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:pdfx="http://ns.adobe.com/pdfx/1.3/">
         <pdfx:ElsevierWebPDFSpecifications>7.0</pdfx:ElsevierWebPDFSpecifications>
         <pdfx:CrossmarkMajorVersionDate>2010-04-23</pdfx:CrossmarkMajorVersionDate>
         <pdfx:CrossmarkDomainExclusive>true</pdfx:CrossmarkDomainExclusive>
         <pdfx:doi>10.1016/j.jcyt.2023.08.008</pdfx:doi>
         <pdfx:robots>noindex</pdfx:robots>
         <pdfx:AuthoritativeDomain>
            <rdf:Bag>
               <rdf:li>sciencedirect.com</rdf:li>
               <rdf:li>elsevier.com</rdf:li>
            </rdf:Bag>
         </pdfx:AuthoritativeDomain>
         <pdfx:CrossMarkDomains>
            <rdf:Seq>
               <rdf:li>sciencedirect.com</rdf:li>
               <rdf:li>elsevier.com</rdf:li>
            </rdf:Seq>
         </pdfx:CrossMarkDomains>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:jav="http://www.niso.org/schemas/jav/1.0/">
         <jav:journal_article_version>VoR</jav:journal_article_version>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:crossmark_1_="http://crossref.org/crossmark/1.0/">
         <crossmark_1_:CrossmarkDomainExclusive>true</crossmark_1_:CrossmarkDomainExclusive>
         <crossmark_1_:MajorVersionDate>2010-04-23</crossmark_1_:MajorVersionDate>
         <crossmark_1_:DOI>10.1016/j.jcyt.2023.08.008</crossmark_1_:DOI>
         <crossmark_1_:CrossMarkDomains>
            <rdf:Seq>
               <rdf:li>sciencedirect.com</rdf:li>
               <rdf:li>elsevier.com</rdf:li>
            </rdf:Seq>
         </crossmark_1_:CrossMarkDomains>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xmpRights="http://ns.adobe.com/xap/1.0/rights/">
         <xmpRights:Marked>True</xmpRights:Marked>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:ali="http://www.niso.org/schemas/ali/1.0/">
         <ali:license_ref>
            <rdf:Bag>
               <rdf:li rdf:parseType="Resource">
                  <ali:uri>http://creativecommons.org/licenses/by-nc-nd/4.0/</ali:uri>
               </rdf:li>
            </rdf:Bag>
         </ali:license_ref>
      </rdf:Description>
   </rdf:RDF>
</x:xmpmeta>
   Pages: 
    Page: 
     Label: 418
     Sequence: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 496, 579, 524, 608
      Annotation: 
       Subtype: Link
       Rect: 139, 538, 143, 549
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 145, 538, 150, 549
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 151, 533, 156, 544
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 255, 538, 260, 549
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 348, 538, 353, 549
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 446, 538, 450, 549
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 94, 525, 99, 536
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 173, 525, 177, 536
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 245, 525, 250, 536
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 343, 525, 348, 536
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 412, 525, 417, 536
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 100, 512, 105, 523
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 107, 512, 111, 523
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 113, 512, 118, 523
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 119, 508, 124, 518
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 124, 508, 128, 518
       Destination: 558
      Annotation: 
       Subtype: Link
       Rect: 392, 213, 550, 221
      Annotation: 
       Subtype: Link
       Rect: 404, 178, 414, 186
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 502, 146, 513, 154
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 94, 83, 143, 89
      Annotation: 
       Subtype: Link
       Rect: 209, 83, 249, 89
      Annotation: 
       Subtype: Link
       Rect: 32, 66, 153, 72
      Annotation: 
       Subtype: Link
       Rect: 35, 48, 183, 55
      Annotation: 
       Subtype: Link
       Rect: 245, 749, 323, 755
      Annotation: 
       Subtype: Link
       Rect: 328, 749, 339, 755
      Annotation: 
       Subtype: Link
       Rect: 294, 721, 345, 729
      Annotation: 
       Subtype: Link
       Rect: 259, 664, 356, 672
    Page: 
     Label: 419
     Sequence: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 263, 643, 267, 651
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 269, 643, 274, 651
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 94, 549, 98, 557
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 100, 549, 105, 557
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 239, 507, 249, 515
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 89, 423, 99, 431
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 136, 392, 143, 400
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 149, 392, 161, 400
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 177, 392, 189, 400
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 195, 392, 207, 400
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 224, 392, 235, 400
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 242, 392, 253, 400
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 45, 381, 54, 389
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 55, 381, 64, 389
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 45, 371, 54, 379
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 55, 371, 64, 379
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 118, 266, 128, 274
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 129, 266, 139, 274
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 170, 172, 184, 180
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 355, 460, 382, 468
       Destination: 1
      Annotation: 
       Subtype: Link
       Rect: 545, 408, 560, 416
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 447, 397, 461, 405
       Destination: 175
    Page: 
     Label: 420
     Sequence: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 231, 172, 257, 180
       Destination: 1
    Page: 
     Label: 421
     Sequence: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 161, 591, 170, 599
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 172, 591, 181, 599
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 213, 340, 228, 347
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 369, 151, 402, 159
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 413, 130, 444, 138
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 361, 99, 392, 107
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 509, 78, 539, 86
       Destination: 41
      Annotation: 
       Subtype: Link
       Rect: 488, 47, 519, 55
       Destination: 55
    Page: 
     Label: 422
     Sequence: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 242, 360, 274, 368
       Destination: 55
      Annotation: 
       Subtype: Link
       Rect: 54, 277, 83, 285
       Destination: 55
      Annotation: 
       Subtype: Link
       Rect: 481, 319, 507, 327
       Destination: 55
      Annotation: 
       Subtype: Link
       Rect: 512, 245, 542, 253
       Destination: 71
      Annotation: 
       Subtype: Link
       Rect: 513, 224, 543, 232
       Destination: 71
      Annotation: 
       Subtype: Link
       Rect: 414, 183, 444, 191
       Destination: 71
      Annotation: 
       Subtype: Link
       Rect: 431, 99, 460, 107
       Destination: 71
    Page: 
     Label: 423
     Sequence: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 390, 476, 400, 484
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 540, 466, 550, 474
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 471, 371, 481, 379
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 466, 246, 475, 254
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 477, 246, 486, 254
       Destination: 175
    Page: 
     Label: 424
     Sequence: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 424, 156, 439, 164
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 523, 114, 537, 122
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 369, 104, 384, 112
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 477, 104, 492, 112
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 342, 52, 357, 60
       Destination: 175
    Page: 
     Label: 425
     Sequence: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 151, 695, 156, 703
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 158, 695, 167, 703
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 169, 695, 178, 703
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 180, 695, 189, 703
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 246, 674, 261, 682
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 187, 622, 201, 630
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 45, 517, 54, 525
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 56, 517, 65, 525
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 71, 517, 80, 525
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 82, 517, 91, 525
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 93, 517, 102, 525
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 104, 517, 113, 525
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 109, 507, 124, 515
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 241, 277, 250, 285
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 252, 277, 261, 285
       Destination: 175
      Annotation: 
       Subtype: Link
       Rect: 202, 141, 247, 149
       Destination: 83
      Annotation: 
       Subtype: Link
       Rect: 326, 549, 562, 556
      Annotation: 
       Subtype: Link
       Rect: 326, 541, 523, 548
      Annotation: 
       Subtype: Link
       Rect: 326, 533, 373, 540
      Annotation: 
       Subtype: Link
       Rect: 376, 533, 380, 540
      Annotation: 
       Subtype: Link
       Rect: 383, 533, 562, 540
      Annotation: 
       Subtype: Link
       Rect: 326, 525, 481, 532
      Annotation: 
       Subtype: Link
       Rect: 326, 517, 360, 524
      Annotation: 
       Subtype: Link
       Rect: 364, 517, 389, 524
      Annotation: 
       Subtype: Link
       Rect: 393, 517, 419, 524
      Annotation: 
       Subtype: Link
       Rect: 422, 517, 458, 524
      Annotation: 
       Subtype: Link
       Rect: 461, 517, 562, 524
      Annotation: 
       Subtype: Link
       Rect: 326, 509, 562, 516
      Annotation: 
       Subtype: Link
       Rect: 326, 501, 438, 508
      Annotation: 
       Subtype: Link
       Rect: 326, 493, 562, 500
      Annotation: 
       Subtype: Link
       Rect: 326, 485, 376, 492
      Annotation: 
       Subtype: Link
       Rect: 344, 461, 562, 468
      Annotation: 
       Subtype: Link
       Rect: 326, 453, 558, 460
      Annotation: 
       Subtype: Link
       Rect: 326, 422, 562, 428
      Annotation: 
       Subtype: Link
       Rect: 326, 414, 562, 420
      Annotation: 
       Subtype: Link
       Rect: 326, 406, 562, 412
      Annotation: 
       Subtype: Link
       Rect: 326, 398, 405, 404
      Annotation: 
       Subtype: Link
       Rect: 326, 390, 562, 396
      Annotation: 
       Subtype: Link
       Rect: 326, 382, 562, 388
      Annotation: 
       Subtype: Link
       Rect: 326, 374, 402, 380
      Annotation: 
       Subtype: Link
       Rect: 326, 366, 562, 372
      Annotation: 
       Subtype: Link
       Rect: 326, 358, 562, 364
      Annotation: 
       Subtype: Link
       Rect: 326, 350, 499, 356
      Annotation: 
       Subtype: Link
       Rect: 326, 342, 562, 348
      Annotation: 
       Subtype: Link
       Rect: 329, 334, 562, 340
      Annotation: 
       Subtype: Link
       Rect: 326, 326, 562, 332
      Annotation: 
       Subtype: Link
       Rect: 326, 318, 388, 324
      Annotation: 
       Subtype: Link
       Rect: 326, 310, 562, 316
      Annotation: 
       Subtype: Link
       Rect: 326, 302, 562, 308
      Annotation: 
       Subtype: Link
       Rect: 326, 294, 548, 300
      Annotation: 
       Subtype: Link
       Rect: 326, 286, 562, 292
      Annotation: 
       Subtype: Link
       Rect: 326, 278, 562, 285
      Annotation: 
       Subtype: Link
       Rect: 326, 270, 476, 277
      Annotation: 
       Subtype: Link
       Rect: 326, 262, 562, 269
      Annotation: 
       Subtype: Link
       Rect: 326, 254, 562, 261
      Annotation: 
       Subtype: Link
       Rect: 326, 246, 562, 253
      Annotation: 
       Subtype: Link
       Rect: 326, 238, 494, 245
      Annotation: 
       Subtype: Link
       Rect: 326, 230, 562, 237
      Annotation: 
       Subtype: Link
       Rect: 326, 222, 562, 229
      Annotation: 
       Subtype: Link
       Rect: 326, 214, 473, 221
      Annotation: 
       Subtype: Link
       Rect: 326, 206, 562, 213
      Annotation: 
       Subtype: Link
       Rect: 326, 198, 562, 205
      Annotation: 
       Subtype: Link
       Rect: 326, 190, 562, 197
      Annotation: 
       Subtype: Link
       Rect: 326, 183, 335, 189
      Annotation: 
       Subtype: Link
       Rect: 326, 175, 562, 181
      Annotation: 
       Subtype: Link
       Rect: 326, 167, 562, 173
      Annotation: 
       Subtype: Link
       Rect: 326, 159, 562, 165
      Annotation: 
       Subtype: Link
       Rect: 326, 151, 380, 157
      Annotation: 
       Subtype: Link
       Rect: 326, 143, 562, 149
      Annotation: 
       Subtype: Link
       Rect: 326, 135, 562, 141
      Annotation: 
       Subtype: Link
       Rect: 326, 127, 470, 133
      Annotation: 
       Subtype: Link
       Rect: 326, 119, 562, 125
      Annotation: 
       Subtype: Link
       Rect: 326, 111, 562, 117
      Annotation: 
       Subtype: Link
       Rect: 326, 103, 498, 109
      Annotation: 
       Subtype: Link
       Rect: 326, 95, 562, 101
      Annotation: 
       Subtype: Link
       Rect: 326, 87, 562, 93
      Annotation: 
       Subtype: Link
       Rect: 326, 79, 562, 85
      Annotation: 
       Subtype: Link
       Rect: 326, 71, 469, 77
      Annotation: 
       Subtype: Link
       Rect: 326, 63, 562, 69
      Annotation: 
       Subtype: Link
       Rect: 326, 55, 562, 61
      Annotation: 
       Subtype: Link
       Rect: 326, 47, 403, 53
    Page: 
     Label: 426
     Sequence: 9
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 48, 727, 283, 733
      Annotation: 
       Subtype: Link
       Rect: 48, 719, 265, 725
      Annotation: 
       Subtype: Link
       Rect: 48, 711, 283, 717
      Annotation: 
       Subtype: Link
       Rect: 48, 703, 68, 709
      Annotation: 
       Subtype: Link
       Rect: 72, 703, 283, 709
      Annotation: 
       Subtype: Link
       Rect: 48, 695, 283, 701
      Annotation: 
       Subtype: Link
       Rect: 48, 687, 94, 693
      Annotation: 
       Subtype: Link
       Rect: 48, 679, 283, 686
      Annotation: 
       Subtype: Link
       Rect: 48, 671, 283, 678
      Annotation: 
       Subtype: Link
       Rect: 48, 663, 136, 670
      Annotation: 
       Subtype: Link
       Rect: 141, 663, 283, 670
      Annotation: 
       Subtype: Link
       Rect: 48, 655, 142, 662
      Annotation: 
       Subtype: Link
       Rect: 47, 647, 184, 654
      Annotation: 
       Subtype: Link
       Rect: 188, 647, 283, 654
      Annotation: 
       Subtype: Link
       Rect: 47, 639, 283, 646
      Annotation: 
       Subtype: Link
       Rect: 47, 631, 270, 638
      Annotation: 
       Subtype: Link
       Rect: 48, 623, 283, 630
      Annotation: 
       Subtype: Link
       Rect: 48, 615, 283, 622
      Annotation: 
       Subtype: Link
       Rect: 48, 607, 233, 614
      Annotation: 
       Subtype: Link
       Rect: 236, 607, 283, 614
      Annotation: 
       Subtype: Link
       Rect: 48, 599, 283, 606
      Annotation: 
       Subtype: Link
       Rect: 48, 591, 283, 598
      Annotation: 
       Subtype: Link
       Rect: 48, 583, 106, 590
      Annotation: 
       Subtype: Link
       Rect: 48, 576, 283, 582
      Annotation: 
       Subtype: Link
       Rect: 48, 568, 283, 574
      Annotation: 
       Subtype: Link
       Rect: 48, 560, 143, 566
      Annotation: 
       Subtype: Link
       Rect: 48, 552, 57, 558
      Annotation: 
       Subtype: Link
       Rect: 61, 552, 144, 558
      Annotation: 
       Subtype: Link
       Rect: 147, 552, 175, 558
      Annotation: 
       Subtype: Link
       Rect: 179, 552, 204, 558
      Annotation: 
       Subtype: Link
       Rect: 208, 552, 283, 558
      Annotation: 
       Subtype: Link
       Rect: 48, 544, 283, 550
      Annotation: 
       Subtype: Link
       Rect: 48, 536, 283, 542
      Annotation: 
       Subtype: Link
       Rect: 48, 528, 166, 534
      Annotation: 
       Subtype: Link
       Rect: 48, 520, 283, 526
      Annotation: 
       Subtype: Link
       Rect: 48, 512, 283, 518
      Annotation: 
       Subtype: Link
       Rect: 317, 727, 552, 733
      Annotation: 
       Subtype: Link
       Rect: 317, 719, 403, 725
      Annotation: 
       Subtype: Link
       Rect: 317, 711, 552, 717
      Annotation: 
       Subtype: Link
       Rect: 317, 703, 552, 709
      Annotation: 
       Subtype: Link
       Rect: 317, 695, 405, 701
      Annotation: 
       Subtype: Link
       Rect: 317, 687, 552, 693
      Annotation: 
       Subtype: Link
       Rect: 317, 679, 552, 686
      Annotation: 
       Subtype: Link
       Rect: 317, 671, 534, 678
      Annotation: 
       Subtype: Link
       Rect: 317, 639, 552, 646
      Annotation: 
       Subtype: Link
       Rect: 317, 631, 552, 638
      Annotation: 
       Subtype: Link
       Rect: 317, 623, 552, 630
      Annotation: 
       Subtype: Link
       Rect: 317, 615, 359, 622
      Annotation: 
       Subtype: Link
       Rect: 317, 607, 552, 614
      Annotation: 
       Subtype: Link
       Rect: 317, 599, 552, 606
      Annotation: 
       Subtype: Link
       Rect: 317, 591, 445, 598
      Annotation: 
       Subtype: Link
       Rect: 317, 583, 552, 590
      Annotation: 
       Subtype: Link
       Rect: 317, 576, 552, 582
      Annotation: 
       Subtype: Link
       Rect: 317, 568, 552, 574
      Annotation: 
       Subtype: Link
       Rect: 317, 560, 426, 566
      Annotation: 
       Subtype: Link
       Rect: 317, 552, 552, 558
      Annotation: 
       Subtype: Link
       Rect: 317, 544, 552, 550
      Annotation: 
       Subtype: Link
       Rect: 317, 536, 363, 542
      Annotation: 
       Subtype: Link
       Rect: 317, 528, 552, 534
      Annotation: 
       Subtype: Link
       Rect: 317, 520, 552, 526
      Annotation: 
       Subtype: Link
       Rect: 317, 512, 359, 518
  Checksum: c53d8ae5
   Type: CRC32
  Checksum: fcba9972bba5662fd6340a0339eacd74
   Type: MD5
  Checksum: 29f1cd3dedb2d6d43831ac778239f2c9fd04dd99
   Type: SHA-1
  Checksum: dcbd0a0aef89b410508c1ecd04f895b77f6b1a8d5516f3984c8d88319e40682b
   Type: SHA-256