f2a36e2566eb22da31204484b2bb7b1a  pmc_10609949.pdf
3aed20e1b4557944f3f0bd5ccbcef9e622343568  pmc_10609949.pdf
de1354a86852706427fcc2490bf21ff0f98675bd560d4dc558737e002c6fe781  pmc_10609949.pdf

Title:           Functionalizing Dendrimers for Targeted Delivery of Bioactive Molecules to Macrophages: A Potential Treatment for Mycobacterium tuberculosis Infection—A Review
Subject:         Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates that despite the progress of modern medicine, improvements in diagnostics, and the development of drug susceptibility tests, TB remains a global threat to public health. In this sense, host-directed therapy may provide a new approach to the cure of TB, and the expression of miRNAs has been correlated with a change in the concentration of various inflammatory mediators whose concentrations are responsible for the pathophysiology of M. tuberculosis infection. Thus, the administration of miRNAs may help to modulate the immune response of organisms. However, direct administration of miRNAs, without adequate encapsulation, exposes nucleic acids to the activity of cytosolic nucleases, limiting their application. Dendrimers are a family of highly branched molecules with a well-defined architecture and a branched conformation which gives rise to cavities that facilitate physical immobilization, and functional groups that allow chemical interaction with molecules of interest. Additionally, dendrimers can be easily functionalized to target different cells, macrophages among them. In this sense, various studies have proposed the use of different cell receptors as target molecules to aim dendrimers at macrophages and thus release drugs or nucleic acids in the cell of interest. Based on the considerations, the primary objective of this review is to comprehensively explore the potential of functionalized dendrimers as delivery vectors for miRNAs and other therapeutic agents into macrophages. This work aims to provide insights into the use of functionalized dendrimers as an innovative approach for TB treatment, focusing on their ability to target and deliver therapeutic cargo to macrophages.
Keywords:        tuberculosis; Mycobacterium tuberculosis; miRNA; dendrimers; host directed therapy
Author:          Claudia Sanhueza, Daniela Vergara, Catalina Chávez-Aravena, Felipe Gálvez-Jiron, Emigdio Chavez-Angel and Alejandro Castro-Alvarez
Creator:         LaTeX with hyperref
Producer:        pdfTeX-1.40.21
CreationDate:    Mon Oct  9 09:12:52 2023 CEST
ModDate:         Mon Oct  9 09:15:46 2023 CEST
Custom Metadata: no
Metadata Stream: no
Tagged:          no
UserProperties:  no
Suspects:        no
Form:            none
JavaScript:      no
Pages:           16
Encrypted:       no
Page size:       595.276 x 841.89 pts (A4)
Page rot:        0
File size:       3430255 bytes
Optimized:       no
PDF version:     1.7


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
AQGLLD+URWPalladioL-Bold             Type 1            Custom           yes yes no      10  0
UQCLUO+URWPalladioL-Roma             Type 1            Custom           yes yes no      15  0
WHCNOB+URWPalladioL-Ital             Type 1            Custom           yes yes no      19  0
VSDRPX+URWPalladioL-BoldItal         Type 1            Custom           yes yes no      23  0
MUIGQP+VnURWPalladioL                Type 1            Custom           yes yes no      27  0
AIQCCL+VnURWPalladioL-Bold           Type 1            Custom           yes yes no      32  0
VWRBXB+TimesNewRomanPS-BoldItalicMT  Type 1C           WinAnsi          yes yes no      50  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes     74  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes     82  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes     90  0
LHCXDL+EURM10                        Type 1            Builtin          yes yes no     105  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    111  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    119  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    127  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    141  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    149  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    157  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    198  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    206  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    214  0
EUQOAW+EURM7                         Type 1            Builtin          yes yes no     226  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    238  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    246  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    254  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    265  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    273  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    281  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    298  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    306  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    314  0
CIDFont+F3                           CID TrueType      Identity-H       yes no  yes    329  0
CIDFont+F1                           CID TrueType      Identity-H       yes no  yes    337  0
CIDFont+F2                           CID TrueType      Identity-H       yes no  yes    345  0
QGUKZH+CMSY10                        Type 1            Builtin          yes yes no     372  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2025-02-17 17:02:01 CET
 RepresentationInformation: pmc_10609949.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2025-02-08 03:11:27 CET
  Size: 3430255
  Format: PDF
  Version: 1.7
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  PDFMetadata: 
   Objects: 641
   FreeObjects: 1
   IncrementalUpdates: 0
   DocumentCatalog: 
    PageLayout: SinglePage
    PageMode: UseNone
    Outlines: 
     Item: 
      Title: Introduction 
      Destination: section.1
      Children: 
       Item: 
        Title: TB Current Therapies 
        Destination: subsection.1.1
       Item: 
        Title: miRNA Therapies 
        Destination: subsection.1.2
     Item: 
      Title: Dendrimers as Carriers 
      Destination: section.2
      Children: 
       Item: 
        Title: Current Studies Using Dendrimers in TB 
        Destination: subsection.2.1
       Item: 
        Title: Dendrimers for Gene Therapy 
        Destination: subsection.2.2
       Item: 
        Title: Targeting Dendrimers to Alveolar Macrophages 
        Destination: subsection.2.3
        Children: 
         Item: 
          Title: Mannose Functionalization 
          Destination: subsubsection.2.3.1
         Item: 
          Title: Tuftsin Functionalization 
          Destination: subsubsection.2.3.2
     Item: 
      Title: General Outlooks and Future Perspectives 
      Destination: section.3
     Item: 
      Title: References
      Destination: section.4
   Info: 
    Title: Functionalizing Dendrimers for Targeted Delivery of Bioactive Molecules to Macrophages: A Potential Treatment for Mycobacterium tuberculosis Infection A Review
    Author: Claudia Sanhueza, Daniela Vergara, Catalina Chávez-Aravena, Felipe Gálvez-Jiron, Emigdio Chavez-Angel and Alejandro Castro-Alvarez
    Subject: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates that despite the progress of modern medicine, improvements in diagnostics, and the development of drug susceptibility tests, TB remains a global threat to public health. In this sense, host-directed therapy may provide a new approach to the cure of TB, and the expression of miRNAs has been correlated with a change in the concentration of various inflammatory mediators whose concentrations are responsible for the pathophysiology of M. tuberculosis infection. Thus, the administration of miRNAs may help to modulate the immune response of organisms. However, direct administration of miRNAs, without adequate encapsulation, exposes nucleic acids to the activity of cytosolic nucleases, limiting their application. Dendrimers are a family of highly branched molecules with a well-defined architecture and a branched conformation which gives rise to cavities that facilitate physical immobilization, and functional groups that allow chemical interaction with molecules of interest. Additionally, dendrimers can be easily functionalized to target different cells, macrophages among them. In this sense, various studies have proposed the use of different cell receptors as target molecules to aim dendrimers at macrophages and thus release drugs or nucleic acids in the cell of interest. Based on the considerations, the primary objective of this review is to comprehensively explore the potential of functionalized dendrimers as delivery vectors for miRNAs and other therapeutic agents into macrophages. This work aims to provide insights into the use of functionalized dendrimers as an innovative approach for TB treatment, focusing on their ability to target and deliver therapeutic cargo to macrophages.
    Keywords: tuberculosis; Mycobacterium tuberculosis; miRNA; dendrimers; host directed therapy
    Creator: LaTeX with hyperref
    Producer: pdfTeX-1.40.21
    CreationDate: Mon Oct 09 09:12:52 CEST 2023
    ModDate: Mon Oct 09 09:15:46 CEST 2023
   ID: 0x9e1af4959f2ec5b8139c4178875cdef2, 0x9e1af4959f2ec5b8139c4178875cdef2
   Filters: 
    FilterPipeline: FlateDecode
   Fonts: 
    Type1: 
     Font: 
      BaseFont: AIQCCL+VnURWPalladioL-Bold
      FontSubset: true
      FirstChar: 161
      LastChar: 161
      FontDescriptor: 
       FontName: AIQCCL+VnURWPalladioL-Bold
       Flags: Symbolic
       FontBBox: -152, -301, 1000, 935
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: EUQOAW+EURM7
      FontSubset: true
      FirstChar: 22
      LastChar: 22
      FontDescriptor: 
       FontName: EUQOAW+EURM7
       Flags: Symbolic
       FontBBox: -5, -243, 1229, 720
       FontFile: true
     Font: 
      BaseFont: WHCNOB+URWPalladioL-Ital
      FontSubset: true
      FirstChar: 46
      LastChar: 121
      FontDescriptor: 
       FontName: WHCNOB+URWPalladioL-Ital
       Flags: Symbolic
       FontBBox: -170, -305, 1010, 941
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: QGUKZH+CMSY10
      FontSubset: true
      FirstChar: 14
      LastChar: 14
      FontDescriptor: 
       FontName: QGUKZH+CMSY10
       Flags: Symbolic
       FontBBox: -29, -960, 1116, 775
       FontFile: true
     Font: 
      BaseFont: VSDRPX+URWPalladioL-BoldItal
      FontSubset: true
      FirstChar: 77
      LastChar: 121
      FontDescriptor: 
       FontName: VSDRPX+URWPalladioL-BoldItal
       Flags: Symbolic
       FontBBox: -170, -300, 1073, 935
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: LHCXDL+EURM10
      FontSubset: true
      FirstChar: 11
      LastChar: 20
      FontDescriptor: 
       FontName: LHCXDL+EURM10
       Flags: Symbolic
       FontBBox: -32, -243, 1060, 720
       FontFile: true
     Font: 
      BaseFont: AQGLLD+URWPalladioL-Bold
      FontSubset: true
      FirstChar: 3
      LastChar: 151
      FontDescriptor: 
       FontName: AQGLLD+URWPalladioL-Bold
       Flags: Symbolic
       FontBBox: -152, -301, 1000, 935
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: MUIGQP+VnURWPalladioL
      FontSubset: true
      FirstChar: 146
      LastChar: 226
      FontDescriptor: 
       FontName: MUIGQP+VnURWPalladioL
       Flags: Symbolic
       FontBBox: -166, -283, 1021, 943
       FontFile: true
      EncodingDictionary: 
       Differences: true
     Font: 
      BaseFont: UQCLUO+URWPalladioL-Roma
      FontSubset: true
      FirstChar: 2
      LastChar: 252
      FontDescriptor: 
       FontName: UQCLUO+URWPalladioL-Roma
       Flags: Symbolic
       FontBBox: -166, -283, 1021, 943
       FontFile: true
      EncodingDictionary: 
       Differences: true
   Pages: 
    Page: 
     Sequence: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 82, 279, 152, 288
      Annotation: 
       Subtype: Link
       Rect: 34, 267, 99, 276
      Annotation: 
       Subtype: Link
       Rect: 34, 164, 96, 186
      Annotation: 
       Subtype: Link
       Rect: 126, 90, 154, 99
      Annotation: 
       Subtype: Link
       Rect: 34, 78, 147, 87
      Annotation: 
       Subtype: Link
       Rect: 34, 757, 167, 793
      Annotation: 
       Subtype: Link
       Rect: 515, 757, 560, 793
      Annotation: 
       Subtype: Link
       Rect: 131, 642, 142, 655
      Annotation: 
       Subtype: Link
       Rect: 232, 642, 243, 655
      Annotation: 
       Subtype: Link
       Rect: 147, 629, 158, 643
      Annotation: 
       Subtype: Link
       Rect: 301, 629, 313, 643
      Annotation: 
       Subtype: Link
       Rect: 364, 130, 371, 139
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 223, 105, 230, 114
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 141, 17, 275, 28
      Annotation: 
       Subtype: Link
       Rect: 378, 17, 560, 28
      Annotation: 
       Subtype: Link
       Rect: 34, 400, 87, 419
    Page: 
     Sequence: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 389, 685, 396, 694
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 458, 648, 465, 657
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 315, 519, 322, 531
       ActionDest: 69
      Annotation: 
       Subtype: Link
       Rect: 370, 509, 377, 519
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 195, 216, 202, 225
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 458, 178, 465, 187
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 480, 165, 487, 175
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 295, 128, 302, 137
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 549, 90, 556, 99
       ActionDest: 369
    Page: 
     Sequence: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 365, 710, 372, 719
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 539, 685, 551, 694
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 384, 648, 391, 657
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 392, 648, 404, 657
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 404, 648, 416, 657
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 466, 610, 478, 619
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 467, 534, 474, 543
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 475, 534, 487, 543
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 464, 484, 476, 493
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 476, 484, 488, 493
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 298, 396, 305, 405
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 329, 359, 341, 368
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 432, 321, 444, 330
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 445, 321, 457, 330
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 409, 296, 421, 305
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 462, 233, 474, 242
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 222, 167, 229, 179
       ActionDest: 102
      Annotation: 
       Subtype: Link
       Rect: 375, 145, 387, 154
       ActionDest: 369
    Page: 
     Sequence: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 192, 723, 204, 732
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 538, 432, 549, 440
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 368, 348, 380, 357
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 420, 310, 432, 320
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 544, 286, 556, 294
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 397, 235, 409, 244
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 486, 210, 498, 219
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 278, 160, 290, 169
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 381, 122, 393, 131
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 412, 110, 424, 119
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 404, 97, 416, 106
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 256, 59, 268, 69
       ActionDest: 369
    Page: 
     Sequence: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 332, 710, 344, 719
       ActionDest: 369
      Annotation: 
       Subtype: Link
       Rect: 436, 685, 448, 694
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 483, 660, 495, 669
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 379, 635, 390, 644
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 344, 610, 356, 619
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 274, 585, 286, 594
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 289, 585, 301, 594
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 215, 535, 227, 544
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 445, 522, 457, 531
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 344, 456, 351, 468
       ActionDest: 136
      Annotation: 
       Subtype: Link
       Rect: 358, 459, 370, 468
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 373, 459, 385, 468
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 468, 434, 480, 443
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 278, 409, 290, 418
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 432, 396, 444, 405
       ActionDest: 376
    Page: 
     Sequence: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 544, 723, 556, 732
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 529, 673, 541, 682
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 258, 647, 270, 657
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 190, 585, 202, 594
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 245, 582, 252, 594
       ActionDest: 136
      Annotation: 
       Subtype: Link
       Rect: 272, 582, 279, 594
       ActionDest: 193
      Annotation: 
       Subtype: Link
       Rect: 376, 362, 388, 371
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 202, 324, 214, 333
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 280, 311, 292, 320
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 254, 223, 266, 233
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 365, 223, 377, 233
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 520, 98, 532, 107
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 535, 98, 547, 107
       ActionDest: 376
    Page: 
     Sequence: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 224, 670, 236, 679
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 328, 670, 340, 679
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 427, 670, 439, 679
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 252, 644, 264, 654
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 361, 607, 373, 616
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 481, 594, 493, 603
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 212, 554, 218, 566
       ActionDest: 223
      Annotation: 
       Subtype: Link
       Rect: 544, 459, 552, 466
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 544, 412, 552, 419
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 544, 363, 552, 370
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 544, 305, 552, 311
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 544, 248, 552, 255
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 544, 181, 552, 188
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 544, 108, 552, 115
       ActionDest: 379
    Page: 
     Sequence: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 414, 707, 426, 716
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 427, 707, 439, 716
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 492, 619, 504, 629
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 544, 569, 556, 578
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 463, 506, 475, 516
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 476, 506, 488, 516
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 531, 469, 543, 478
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 502, 431, 513, 440
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 454, 394, 466, 403
       ActionDest: 376
      Annotation: 
       Subtype: Link
       Rect: 280, 353, 287, 365
       ActionDest: 233
      Annotation: 
       Subtype: Link
       Rect: 455, 353, 462, 365
       ActionDest: 233
      Annotation: 
       Subtype: Link
       Rect: 544, 318, 556, 327
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 533, 293, 545, 302
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 298, 280, 310, 290
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 277, 230, 289, 239
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 297, 167, 309, 177
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 366, 127, 373, 139
       ActionDest: 233
    Page: 
     Sequence: 9
    Page: 
     Sequence: 10
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 401, 685, 413, 694
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 309, 585, 321, 594
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 491, 585, 503, 594
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 530, 484, 542, 493
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 211, 371, 223, 380
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 216, 333, 228, 342
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 393, 283, 405, 292
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 279, 220, 291, 229
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 197, 69, 209, 79
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 209, 70, 221, 79
       ActionDest: 379
    Page: 
     Sequence: 11
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 240, 695, 247, 707
       ActionDest: 293
      Annotation: 
       Subtype: Link
       Rect: 544, 443, 556, 452
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 394, 393, 406, 402
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 324, 368, 336, 377
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 440, 355, 452, 364
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 544, 342, 556, 352
       ActionDest: 382
      Annotation: 
       Subtype: Link
       Rect: 297, 305, 309, 314
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 310, 305, 322, 314
       ActionDest: 382
      Annotation: 
       Subtype: Link
       Rect: 325, 305, 337, 314
       ActionDest: 382
      Annotation: 
       Subtype: Link
       Rect: 476, 242, 488, 251
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 489, 242, 501, 251
       ActionDest: 382
      Annotation: 
       Subtype: Link
       Rect: 501, 242, 513, 251
       ActionDest: 382
      Annotation: 
       Subtype: Link
       Rect: 295, 154, 307, 163
       ActionDest: 379
      Annotation: 
       Subtype: Link
       Rect: 284, 142, 296, 151
       ActionDest: 379
    Page: 
     Sequence: 12
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 413, 594, 420, 606
       ActionDest: 324
      Annotation: 
       Subtype: Link
       Rect: 272, 300, 284, 309
       ActionDest: 382
    Page: 
     Sequence: 13
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 351, 549, 388, 560
      Annotation: 
       Subtype: Link
       Rect: 362, 538, 560, 549
      Annotation: 
       Subtype: Link
       Rect: 56, 526, 280, 537
      Annotation: 
       Subtype: Link
       Rect: 59, 493, 96, 503
      Annotation: 
       Subtype: Link
       Rect: 131, 470, 168, 480
      Annotation: 
       Subtype: Link
       Rect: 180, 446, 218, 457
      Annotation: 
       Subtype: Link
       Rect: 191, 424, 229, 434
      Annotation: 
       Subtype: Link
       Rect: 471, 411, 508, 422
      Annotation: 
       Subtype: Link
       Rect: 295, 365, 333, 376
      Annotation: 
       Subtype: Link
       Rect: 447, 354, 485, 365
      Annotation: 
       Subtype: Link
       Rect: 59, 320, 96, 330
      Annotation: 
       Subtype: Link
       Rect: 59, 286, 96, 296
      Annotation: 
       Subtype: Link
       Rect: 165, 262, 203, 273
      Annotation: 
       Subtype: Link
       Rect: 209, 262, 245, 273
      Annotation: 
       Subtype: Link
       Rect: 339, 239, 376, 250
      Annotation: 
       Subtype: Link
       Rect: 383, 239, 419, 250
      Annotation: 
       Subtype: Link
       Rect: 59, 216, 96, 227
      Annotation: 
       Subtype: Link
       Rect: 190, 182, 227, 192
      Annotation: 
       Subtype: Link
       Rect: 233, 182, 269, 192
      Annotation: 
       Subtype: Link
       Rect: 438, 147, 475, 158
      Annotation: 
       Subtype: Link
       Rect: 263, 124, 301, 135
      Annotation: 
       Subtype: Link
       Rect: 334, 101, 372, 112
      Annotation: 
       Subtype: Link
       Rect: 235, 78, 273, 89
    Page: 
     Sequence: 14
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 426, 722, 463, 733
      Annotation: 
       Subtype: Link
       Rect: 59, 688, 95, 698
      Annotation: 
       Subtype: Link
       Rect: 281, 664, 318, 675
      Annotation: 
       Subtype: Link
       Rect: 324, 664, 360, 675
      Annotation: 
       Subtype: Link
       Rect: 104, 630, 142, 640
      Annotation: 
       Subtype: Link
       Rect: 148, 630, 184, 640
      Annotation: 
       Subtype: Link
       Rect: 519, 606, 557, 617
      Annotation: 
       Subtype: Link
       Rect: 59, 596, 95, 606
      Annotation: 
       Subtype: Link
       Rect: 465, 572, 502, 583
      Annotation: 
       Subtype: Link
       Rect: 254, 549, 291, 560
      Annotation: 
       Subtype: Link
       Rect: 520, 537, 557, 548
      Annotation: 
       Subtype: Link
       Rect: 237, 514, 275, 525
      Annotation: 
       Subtype: Link
       Rect: 193, 492, 230, 502
      Annotation: 
       Subtype: Link
       Rect: 445, 468, 482, 479
      Annotation: 
       Subtype: Link
       Rect: 506, 457, 543, 468
      Annotation: 
       Subtype: Link
       Rect: 251, 422, 289, 433
      Annotation: 
       Subtype: Link
       Rect: 117, 400, 155, 410
      Annotation: 
       Subtype: Link
       Rect: 161, 400, 197, 410
      Annotation: 
       Subtype: Link
       Rect: 184, 377, 221, 387
      Annotation: 
       Subtype: Link
       Rect: 227, 377, 263, 387
      Annotation: 
       Subtype: Link
       Rect: 396, 353, 433, 364
      Annotation: 
       Subtype: Link
       Rect: 440, 353, 476, 364
      Annotation: 
       Subtype: Link
       Rect: 158, 308, 195, 318
      Annotation: 
       Subtype: Link
       Rect: 433, 284, 471, 295
      Annotation: 
       Subtype: Link
       Rect: 118, 262, 155, 272
      Annotation: 
       Subtype: Link
       Rect: 95, 239, 132, 249
      Annotation: 
       Subtype: Link
       Rect: 122, 182, 159, 192
      Annotation: 
       Subtype: Link
       Rect: 163, 147, 201, 157
      Annotation: 
       Subtype: Link
       Rect: 207, 147, 243, 157
      Annotation: 
       Subtype: Link
       Rect: 188, 123, 226, 134
      Annotation: 
       Subtype: Link
       Rect: 232, 123, 268, 134
      Annotation: 
       Subtype: Link
       Rect: 135, 90, 173, 100
      Annotation: 
       Subtype: Link
       Rect: 378, 66, 416, 77
    Page: 
     Sequence: 15
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 451, 722, 488, 733
      Annotation: 
       Subtype: Link
       Rect: 147, 699, 185, 710
      Annotation: 
       Subtype: Link
       Rect: 266, 665, 303, 675
      Annotation: 
       Subtype: Link
       Rect: 434, 641, 472, 652
      Annotation: 
       Subtype: Link
       Rect: 418, 618, 456, 629
      Annotation: 
       Subtype: Link
       Rect: 237, 583, 275, 594
      Annotation: 
       Subtype: Link
       Rect: 281, 583, 317, 594
      Annotation: 
       Subtype: Link
       Rect: 154, 561, 191, 571
      Annotation: 
       Subtype: Link
       Rect: 197, 561, 233, 571
      Annotation: 
       Subtype: Link
       Rect: 59, 527, 96, 537
      Annotation: 
       Subtype: Link
       Rect: 135, 504, 173, 514
      Annotation: 
       Subtype: Link
       Rect: 181, 468, 218, 479
      Annotation: 
       Subtype: Link
       Rect: 224, 468, 260, 479
      Annotation: 
       Subtype: Link
       Rect: 520, 445, 557, 456
      Annotation: 
       Subtype: Link
       Rect: 519, 422, 557, 433
      Annotation: 
       Subtype: Link
       Rect: 425, 399, 462, 410
      Annotation: 
       Subtype: Link
       Rect: 222, 365, 259, 376
      Annotation: 
       Subtype: Link
       Rect: 317, 342, 354, 353
      Annotation: 
       Subtype: Link
       Rect: 412, 330, 450, 341
      Annotation: 
       Subtype: Link
       Rect: 456, 330, 492, 341
      Annotation: 
       Subtype: Link
       Rect: 492, 307, 530, 318
      Annotation: 
       Subtype: Link
       Rect: 215, 284, 252, 295
      Annotation: 
       Subtype: Link
       Rect: 259, 284, 295, 295
      Annotation: 
       Subtype: Link
       Rect: 207, 262, 244, 272
      Annotation: 
       Subtype: Link
       Rect: 245, 227, 282, 238
      Annotation: 
       Subtype: Link
       Rect: 289, 227, 325, 238
      Annotation: 
       Subtype: Link
       Rect: 135, 193, 173, 203
      Annotation: 
       Subtype: Link
       Rect: 167, 159, 204, 169
      Annotation: 
       Subtype: Link
       Rect: 239, 135, 276, 146
      Annotation: 
       Subtype: Link
       Rect: 117, 113, 155, 123
      Annotation: 
       Subtype: Link
       Rect: 228, 89, 266, 100
      Annotation: 
       Subtype: Link
       Rect: 291, 66, 329, 77
    Page: 
     Sequence: 16
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 278, 722, 315, 733
      Annotation: 
       Subtype: Link
       Rect: 334, 699, 371, 710
      Annotation: 
       Subtype: Link
       Rect: 377, 699, 413, 710
      Annotation: 
       Subtype: Link
       Rect: 278, 664, 316, 675
      Annotation: 
       Subtype: Link
       Rect: 322, 664, 358, 675
      Annotation: 
       Subtype: Link
       Rect: 347, 629, 384, 640
      Annotation: 
       Subtype: Link
       Rect: 391, 629, 427, 640
      Annotation: 
       Subtype: Link
       Rect: 398, 606, 435, 617
      Annotation: 
       Subtype: Link
       Rect: 442, 606, 478, 617
      Annotation: 
       Subtype: Link
       Rect: 211, 584, 248, 594
      Annotation: 
       Subtype: Link
       Rect: 167, 550, 204, 560
  Checksum: 42197a9a
   Type: CRC32
  Checksum: f2a36e2566eb22da31204484b2bb7b1a
   Type: MD5
  Checksum: 3aed20e1b4557944f3f0bd5ccbcef9e622343568
   Type: SHA-1
  Checksum: de1354a86852706427fcc2490bf21ff0f98675bd560d4dc558737e002c6fe781
   Type: SHA-256