1. 1 بسم الله الرحمن الرحيم Clinical Epidemiology of Rabies

2. 2 Definition History Etiology

3. 3 A fatal viral disease (encephalomyelitis)A fatal viral disease (encephalomyelitis) In human and most other mammalsIn human and most other mammals One of the most common viral causes of mortalityOne of the most common viral causes of mortality 15 million people annually receiving post-exposure vaccination to prevent the disease.15 million people annually receiving post-exposure vaccination to prevent the disease. Definition

4. 4 55000-100000 deaths occur each year because of rabies.55000-100000 deaths occur each year because of rabies. Rabies is a neglected disease of poor and vulnerable populations whose deaths are rarely reported.Rabies is a neglected disease of poor and vulnerable populations whose deaths are rarely reported. Definition

5. 5 Etiologic agent Rabies virusRabies virus Genus : Lyssavirus (lyssa: rage in Greek)Genus : Lyssavirus (lyssa: rage in Greek) Family : Rabdoviridae familyFamily : Rabdoviridae family Enveloped bullet-shaped virusEnveloped bullet-shaped virus 5 structural proteins5 structural proteins SS RNA, non-segmentedSS RNA, non-segmented

6. 6 Rabies Virus Structure of rabies virus Rabies virus particles

7. 7 Rabies Virus in the Environment Normally, rabies virus cannot live long in a warm, putrefied environment,Normally, rabies virus cannot live long in a warm, putrefied environment, Survives in the body less than 24 hours after death. Survives in the body less than 24 hours after death. A few minutes in direct sunlight will inactivate rabies virus.A few minutes in direct sunlight will inactivate rabies virus.

8. 8 under cool conditions (in refrigerator) it may live for many daysunder cool conditions (in refrigerator) it may live for many days If the virus is frozen at -70oC, it can live for years.If the virus is frozen at -70oC, it can live for years. Rabies virus is no longer active in dried salivaRabies virus is no longer active in dried saliva Is killed by bleach, ethyl alcohol, soap, detergent, and quaternary ammonium compounds.Is killed by bleach, ethyl alcohol, soap, detergent, and quaternary ammonium compounds. Rabies Virus in the Environment

9. 9 Widespread CNS involvement Inoculation, the virus replicates in the striated or connective tissue Enters the peripheral nerves through the neuromuscular junction the neuromuscular junction Spreads to the CNS in the endoneurium of the Schwann cells Pathogenesis of Rabies

10. 10 Pathogenesis of Rabies

11. 11 Descriptive epidemiology and occurrence

12. 12 1)Incubation period 2)Natural couarse 3)Geographical distribution 4)Timeline trend 5)Age, Gender, Occupation, Social situation 6)Predisposing factors 7)Susceptibility & Resistance 8)Secondary attack rate 9)Modes of transmission, period of communicability  Definition and public health importance  Etiologic agents Clinical epidemiology of Rabies  Prevention : primary, secondary, tertiary OCCURRENCE

13. 13 1 -Incubation Period 4 days or 19 years (rarely)4 days or 19 years (rarely) Average : 30-90 daysAverage : 30-90 days Depends on: Depends on: Wound severity Wound site (nerve supply) Distance from the brain Amount & strain of virus

14. 14 محدوده دوره كمون هاري

15. 15 StageDuration Incubation period < 30 days (25%) 30-90 days (50%) 30-90 days (50%) 90-365 days (20%) > 365 days (5%) Prodrome & early symptoms 2-10 days Acute neurologic disease Furious rabies (80%) Furious rabies (80%) Paralytic rabies (20%) Paralytic rabies (20%) 2-7 days Coma, Death 0-14 days Recovery Very rare 2 - Natural course

16. 16 Natural course Exposure (usually from contaminated saliva through animal bites) 30-90 days Incubation Prodromal symptoms (fever, chills, malaise, fatigue, insomnia, anorexia, headache, anxiety and irritability) Up to 10 days Local Neurologic symptoms (pain, paresthesias, weakness) Classic (encephalitic) rabies symptoms -80% cases Paralytic rabies -20% cases Coma, Death ~~~ 100%

17. 17 Rabies/clinical manifestations 5 phases of illness5 phases of illness First phase: asymptomaticFirst phase: asymptomatic Second (prodromal) phaseSecond (prodromal) phase Third phase: neurologic signsThird phase: neurologic signs Forth phase : coma, deathForth phase : coma, death Fifth phase : recoveryFifth phase : recovery

18. 18 Rabies/clinical manifestations First phase: asymptomaticFirst phase: asymptomatic Virus IP: 10-90 days (4d-19yr)Virus IP: 10-90 days (4d-19yr)

19. 19 Second (prodromal) phaseSecond (prodromal) phase 2-10d2-10d Viral invasion of CNS (limbic system, spinal cord, brain stem)Viral invasion of CNS (limbic system, spinal cord, brain stem) Respiratory symptomsRespiratory symptoms Gastrointestinal symptomsGastrointestinal symptoms Behavioral & emotional symptomsBehavioral & emotional symptoms Local pain itching, (50%)Local pain itching, (50%) Rabies/clinical manifestations

20. 20 Third phase: neurologic signsThird phase: neurologic signs Widespread infection of the brainWidespread infection of the brain “Furious”: Aggressiveness, biting, yelling, hallucinating“Furious”: Aggressiveness, biting, yelling, hallucinating Triggered by sensory stimuli HydrophobiaAerophobia Violent diaphragmatic contractions Hyper-reflexia, cholinergic manifestations lacrimation, salivation, mydriasis, pyrexia Rabies/clinical manifestations

21. 21 Forth phase: coma, deathForth phase: coma, death Extensive cortical virus spreadExtensive cortical virus spread Death usually in 7 daysDeath usually in 7 days Respiratory arrestRespiratory arrest MyocarditisMyocarditis Rabies/clinical manifestations

22. 22 Fifth phase: recoveryFifth phase: recovery Rare survivorsRare survivors Atypical presentationsAtypical presentations 1972: bat related, dysarthria, hemiparesis1972: bat related, dysarthria, hemiparesis 1976: dog bite, quadreparesis,myoclonus, cerebellar signs,frontal lobe signs1976: dog bite, quadreparesis,myoclonus, cerebellar signs,frontal lobe signs 1977: Lab worker, aerosol exposure to highly concentrated fixed rabies virus1977: Lab worker, aerosol exposure to highly concentrated fixed rabies virus 1992-1995: 4 Mexican children (3:dog, 1: vampire bat), received vaccine, no Ig1992-1995: 4 Mexican children (3:dog, 1: vampire bat), received vaccine, no Ig Rabies/clinical manifestations

23. 23 Neuropathic pain, radicular pain, objective sensory and motor deficitsNeuropathic pain, radicular pain, objective sensory and motor deficits Choreiform movements of the bitten limb during prodromal phaseChoreiform movements of the bitten limb during prodromal phase Focal brain stem signs, myoclonusFocal brain stem signs, myoclonus Hemiparesis, hemisensory loss, ataxia, vertigoHemiparesis, hemisensory loss, ataxia, vertigo Seizures, ataxiaSeizures, ataxia Non-Classical Rabies/clinical manifestations

24. 24 Rabies/Differential Diagnosis Meningitis/Encephalitis: Japanese, eastern equine, West Nile V., enterovirus 71, Nipah V.Meningitis/Encephalitis: Japanese, eastern equine, West Nile V., enterovirus 71, Nipah V. EpilepsyEpilepsy Drug toxicityDrug toxicity Acute hepatic porphyria, neuropsychiatric disturbancesAcute hepatic porphyria, neuropsychiatric disturbances Substance abuse, acute serotonin syndromeSubstance abuse, acute serotonin syndrome Meningitis/Encephalitis: Japanese, eastern equine, West Nile V., enterovirus 71, Nipah V.Meningitis/Encephalitis: Japanese, eastern equine, West Nile V., enterovirus 71, Nipah V. EpilepsyEpilepsy Drug toxicityDrug toxicity Acute hepatic porphyria, neuropsychiatric disturbancesAcute hepatic porphyria, neuropsychiatric disturbances Substance abuse, acute serotonin syndromeSubstance abuse, acute serotonin syndrome

25. 25 3 – Geographical distribution Rabies occurs in more than 150 countries and territoriesRabies occurs in more than 150 countries and territories Worldwide, more than 55 000 people die of rabies every year mostly in Asia and Africa.Worldwide, more than 55 000 people die of rabies every year mostly in Asia and Africa. 40% of people who are bitten by suspect rabid animals are children 40% of people who are bitten by suspect rabid animals are children Fact Sheet N°99, July 2014

26. 26 3 – Geographical distribution در 44 كشور يا منطقه به مرحله حذف رسيده و موردي گزارش نشده است در 44 كشور يا منطقه به مرحله حذف رسيده و موردي گزارش نشده است قطب جنوب و تعدادي از جزاير، در ساير مناطق جهان عاري از هاري است. قطب جنوب و تعدادي از جزاير، در ساير مناطق جهان عاري از هاري است. در جنوب شرقي آسيا، فيليپين، آفريقا، شبه قاره هند و مناطق گرمسيري آمريكاي جنوبي از شيوع بيشتري برخوردار است در جنوب شرقي آسيا، فيليپين، آفريقا، شبه قاره هند و مناطق گرمسيري آمريكاي جنوبي از شيوع بيشتري برخوردار است

27. 27 وضعيت هاري در ايران تقريباً همه استان ‌ ها كم و بيش با مشكل هاري مواجه هستند تقريباً همه استان ‌ ها كم و بيش با مشكل هاري مواجه هستند بيشترين موارد هاري در : حاشيه درياي خزر حاشيه درياي خزر شمال شرقي شمال شرقي جنوب غربي جنوب غربي

28. 28

29. 29 گزارش 2 مورد ناشي از پيوند قرنيه در ايران

30. 30 گزارش 2 مورد ناشي از پيوند قرنيه در ايران

31. 31 تاثير فصل در بعضي از مناطق گرمسيري، در فصل پاييز و زمستان به دنبال شيوع هاري سگسانان، موارد هاري انساني هم افزايش مي ‌ يابد. در بعضي از مناطق گرمسيري، در فصل پاييز و زمستان به دنبال شيوع هاري سگسانان، موارد هاري انساني هم افزايش مي ‌ يابد.

32. 32 5 – Age, Gender, Occupation, Gender, Occupation, Social conditions Social conditions

33. 33 تاثير سن و جنس قريب دوسوّم تا سه چهارم موارد هاري، در جنس مذكّر و به طور كلي، بيشترين موارد بيماري، در سنين كمتر از 20 سالگي بروز مي ‌ نمايد. 40 % هارگزيدگان را كودكان كمتر از 15 ساله تشكيل مي ‌ دهند ( 2014)

34. 34 6 – Predisposing factors & suitable conditions 6 – Predisposing factors & suitable conditions A bite with prominent salivary contamination (Bare skin (A bite with prominent salivary contamination (Bare skin ( Multiple bitesMultiple bites Bites on the faceBites on the face Salivary contamination of broken skinSalivary contamination of broken skin Mucus contaminationMucus contamination Aerosolization (Respiratory tract)Aerosolization (Respiratory tract)

35. 35 7 – Susceptibility and Resistance All mammals are susceptible All mammals are susceptible Humans are more resistant than several animal species Humans are more resistant than several animal species

36. 36 Susceptibility of various animal to rabies Very High HighModerateLow WolvesHamstersDogsOpossums FoxesSkunksPrimates CoyotesRaccoons Kangaroo rats Domestic cats Cotton rats Rabbits JackalsBats VolesCattle

37. 37 8 – Secondary attack rate با توجه به عدم گزارش مستند انتقال هاري از طريق تماس يا گاز گرفتن انسان و يا وجود گزارش ‌ هاي بسيار ناچيز، مي ‌ توان چنين نتيجه گرفت كه ميزان حملات ثانويه آن از انسان به انسان در حد صِفر تا بسيار پايين، مي ‌ باشد. با توجه به عدم گزارش مستند انتقال هاري از طريق تماس يا گاز گرفتن انسان و يا وجود گزارش ‌ هاي بسيار ناچيز، مي ‌ توان چنين نتيجه گرفت كه ميزان حملات ثانويه آن از انسان به انسان در حد صِفر تا بسيار پايين، مي ‌ باشد.

38. 38 9 - Transmission Bite of the rabid animalsBite of the rabid animals A fresh break in the skinA fresh break in the skin Intact mucous membraneIntact mucous membrane Person to person ?Person to person ? Organ transplantationOrgan transplantation Airborne spread from batsAirborne spread from bats Airborne spread in laboratoryAirborne spread in laboratory

39. 39 Period of communicability In dogs and cats for 3-7 days before onset of clinical signs and throughout the course of the disease In dogs and cats for 3-7 days before onset of clinical signs and throughout the course of the disease 14 days before onset, in Ethiopian dogs14 days before onset, in Ethiopian dogs In bats 12 days before evidence of illnessIn bats 12 days before evidence of illness Skunks, 8 days before...Skunks, 8 days before...

40. 40Reservoir Caribbean: Mongoose ميمون پوزه دراز Europe: Red fox Iran: Wolf Africa: Jackal

41. 41 Global distribution of mammalian rabies reservoirs and vectors

42. 42 Animal bite in Iran

43. 43 Animal bite and human rabies in Iran

44. 44 Animal rabies in Iran

45. 45 Rabid wolves are associated with severe bites and human deaths

46. 46 Raccoons are social animals Well adapted to living at high population densities (urban/suburban) Prefer forested habitat

47. 47 A productive pathogenesis cycle of animal rabies: virus entry into peripheral nerves via a bite, movement to the central nervous system resulting in encephalitis, and transit to the salivary glands, mediating infection of another host. Rupprecht CE et al, The Lancet Infectious Diseases Vol 2 June 2002

48. 48 Foxes maintain rabies from Arctic areas to temperate and tropical latitudes

49. 49 Arctic fox

50. 50 The Jackal is an important candid reservoir of rabies in the old world

51. 51 Hosts 6/7 lyssavirus genotypes Widespread throughout North America, Latin America Infection rates in bats varies (4% to > 15%) Humans encounter bats that are Humans encounter bats that are sick, incapacitated Different bat species vary in their human interaction Primary reservoir for rabies in All continents.

52. 52 Prevention and Control

53. 53 Prevention and Control Primary Prevention:Primary Prevention: Prevention of disease in “well” individuals Prevention of disease in “well” individuals Secondary Prevention:Secondary Prevention: Identification and intervention in early stages of disease Identification and intervention in early stages of disease Tertiary Prevention: Tertiary Prevention: Prevention of further deterioration, reduction in complications Prevention of further deterioration, reduction in complications

54. 54 Primary Prevention: Pre-exposure prophylaxis: Primary Prevention: Pre-exposure prophylaxis: vaccination of people in high risk groups:vaccination of people in high risk groups: VeterinariansVeterinarians Animal handlersAnimal handlers Certain lab workersCertain lab workers Travel to areas where canine rabies is commonTravel to areas where canine rabies is common

55. 55 vaccination : intramuscular,vaccination : intramuscular, 1ml (3 doses): at 0, 7, 21-28 days1ml (3 doses): at 0, 7, 21-28 days Antibodies usually persist for 2 yrsAntibodies usually persist for 2 yrs Repeat titers q6-24 months depending on level of exposureRepeat titers q6-24 months depending on level of exposure Acceptable titer levels are 0.5 IU/mlAcceptable titer levels are 0.5 IU/ml Primary Prevention: Pre-exposure prophylaxis: Primary Prevention: Pre-exposure prophylaxis:

56. 56 Human Diploid Cell Vaccine (HDCV)Human Diploid Cell Vaccine (HDCV) Purified vero cell vaccine (PVRV) Purified chicken embryo cell (PCEC)Purified chicken embryo cell (PCEC) Rabies vaccines

57. 57 Post-exposure wound care Prevent virus in wound from reaching neural tissue Prompt and thorough cleaning: flush wound with soap and water Benzalkonium chloride not superior to soap Update tetanus immunization Treat secondary bacterial infection Do not suture wound if possible

58. 58

59. 59 Exposure other than bite rarely causes infectionExposure other than bite rarely causes infection Prophylaxis to patients with open wound scratch mucous membrane contaminated by : contaminated by : saliva or potentially infectious material from rabid animal Exposure other than bite rarely causes infectionExposure other than bite rarely causes infection Prophylaxis to patients with open wound scratch mucous membrane contaminated by : contaminated by : saliva or potentially infectious material from rabid animal Post-exposure Prophylaxis

60. 60 Prophylaxis to people with sig. exposure to a rabies pt. if scratch bite mucous membrane exposure to saliva or infectious tissue No prophylaxis if casual contact (touching) or exposure to non-infectious material (urine, stool) Post-exposure Prophylaxis Human Exposure with Rabies Post-exposure Prophylaxis Human Exposure with Rabies

61. 61 Standard universal precautions Respiratory precautions Pre-exposure prophylaxis Check the antibody titer (~ 0.5 IU/mL) Exposures to potentially contaminated secretions or tissues should lead to standard PET Post-exposure Prophylaxis اقدامات لازم براي مراقبين (پرستاران، پزشكان... Post-exposure Prophylaxis اقدامات لازم براي مراقبين (پرستاران، پزشكان...

62. 62 Post-exposure immunoprophylaxis Passive and activePassive and active Start ASAP (As soon as possible)Start ASAP (As soon as possible) RIG and rabies vaccineRIG and rabies vaccine Vaccine : one of the 3 types (5 doses), same dose for all agesVaccine : one of the 3 types (5 doses), same dose for all ages 1.0 ml IM at 0, 3, 7, 14, 28 d1.0 ml IM at 0, 3, 7, 14, 28 d Intradermal regimens:used alternativelyIntradermal regimens:used alternatively Avoid gluteal injection: less antibody response than deltoid.Avoid gluteal injection: less antibody response than deltoid. Red Book 2003

63. 63 Human RIG is Given at the same time with the vaccine (ASAP) Dose: 20 IU/kg As much as possible to infiltrate the wound Remainder is given IM (is not the first choice) RIG and vaccine are Give at different sites & in different syringes Purified equine RIG : dose is 40 IU/kg, may need desensitization Post-exposure immunoprophylaxis

64. 64 2 - Secondary Prevention: IdentificationAnd intervention intervention in early stages of disease in early stages of diseaseIdentificationAnd intervention intervention in early stages of disease in early stages of disease

65. 65 Frequently missedFrequently missed Lab tests are non diagnosticLab tests are non diagnostic Hyponatremia: inadequate intake, SIADHHyponatremia: inadequate intake, SIADH hypernatremia,: rarehypernatremia,: rare CSF analysis normal in 1/3 of patients in the 1 st wk of illnessCSF analysis normal in 1/3 of patients in the 1 st wk of illness CSF: viral meningoencephalitisCSF: viral meningoencephalitis EEG and head CT may be normal early in illnessEEG and head CT may be normal early in illness Rabies/DiagnosisRabies/Diagnosis

66. 66 Rabies/DiagnosisRabies/Diagnosis MRI: abnormal, ill defined, increase signal intensity on T-2 imagesMRI: abnormal, ill defined, increase signal intensity on T-2 images Areas involved: brainstem, hippocampi, hypothalami, deep & subcortical white and grey matterAreas involved: brainstem, hippocampi, hypothalami, deep & subcortical white and grey matter

67. 67 Brain tissue: culture, histology for Negri bodiesBrain tissue: culture, histology for Negri bodies Immunohistochemistry on tissueImmunohistochemistry on tissue Brain tissue: ImmunostainBrain tissue: Immunostain Rabies/Diagnosis Tissue studies Rabies/Diagnosis

68. 68 Rabies/Diagnosis Rabies specific antibodies in serum or CSF (RFFIT)Rabies specific antibodies in serum or CSF (RFFIT) Serology positive in serum in 7 days of symptomsSerology positive in serum in 7 days of symptoms Serology positive in CSF in 13 days of symptomsSerology positive in CSF in 13 days of symptoms Rabies vaccine does not cause positive CSF antibodiesRabies vaccine does not cause positive CSF antibodies Molecular studies, monoclonal antibodies in epidemiologic studiesMolecular studies, monoclonal antibodies in epidemiologic studies Hammond GW (Principles and Practice of Pediatric Infectious diseases)

69. 69 Section of rabid human brain processed by the DFA test, showing widespread viral inclusions, staining apple-green in colour Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

70. 70 A neuron from a formalin-fixed section of a brain from a patient with rabies, showing reddish-brown viral inclusions in the cytoplasm. Processed by immunohistochemistry. Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

71. 71 Negri Body in neuron cell (source: CDC) Positive DFA test (Source: CDC Diagnosis of Rabies

72. 72 No specific treatment once symptoms have begun No specific treatment once symptoms have begun Intensive care Intensive care Almost all patients succumb to disease in a few weeks Almost all patients succumb to disease in a few weeks 2 - Secondary Prevention Treatment of Rabies 2 - Secondary Prevention Treatment of Rabies

73. 73 The 3 patients in the 1970s survived The 3 patients in the 1970s survived A child in 1994 which received only rabies vaccineA child in 1994 which received only rabies vaccine No effective drugNo effective drug No benefit of interfrons, Ribavirin & Cytosine arabinosideNo benefit of interfrons, Ribavirin & Cytosine arabinoside Secondary Prevention Treatment of Rabies Secondary Prevention Treatment of Rabies

74. 74 3 - Tertiary Prevention: Surgical interventionSurgical intervention

75. 75 Sources : Mandell, Douglas, Bennett; Principles and Practice of Infectious Diseases, 6 th edition, 2015. Mandell, Douglas, Bennett; Principles and Practice of Infectious Diseases, 6 th edition, 2015. Kasper, Braunwald, Fauci, Hauser, Longo, Jameson : Harrison's Principles of Internal Medicine; 18 th Edition, 2012 Kasper, Braunwald, Fauci, Hauser, Longo, Jameson : Harrison's Principles of Internal Medicine; 18 th Edition, 2012 Feigin, Cherry, Demmler, Kaplan : Textbook of Pediatric Infectious Diseases, 6 th edit., Saunders, 2008. Feigin, Cherry, Demmler, Kaplan : Textbook of Pediatric Infectious Diseases, 6 th edit., Saunders, 2008. David L. Heymann (edit.): Control of Communicable Diseases Manual, 19 th Edition, 2008, David L. Heymann (edit.): Control of Communicable Diseases Manual, 19 th Edition, 2008, CDC Internet Site, 2011 CDC Internet Site, 2011 WHO, WHO, Fact Sheet N°99, September 2014 Tony J. and Leoni G. Causes, Effects, in Animals and Humans Tony J. and Leoni G. Lillian A. Orciari, Epidemiology of Rabies

76. 76 Sources : Rabies Management Guideline, A compendium of rabies control measures and planning strategies compiled by the Maine Rabies Work Group – 2005, pp. 1-107. Rabies Management Guideline, A compendium of rabies control measures and planning strategies compiled by the Maine Rabies Work Group – 2005, pp. 1-107. WHO Expert Consultation on Rabies (2004 : Geneva, Switzerland) WHO Expert Consultation on Rabies : first report.(WHO technical report series ; 931), World Health Organization 2005, PP. 1-121 WHO Expert Consultation on Rabies (2004 : Geneva, Switzerland) WHO Expert Consultation on Rabies : first report.(WHO technical report series ; 931), World Health Organization 2005, PP. 1-121 Arjun Srinivasan, Elizabeth C. Burton... Transmission of Rabies Virus from an Organ Donor to Four Transplant Recipients, New England Journal of Medicine, 2005; 352: 1103-11. Arjun Srinivasan, Elizabeth C. Burton... Transmission of Rabies Virus from an Organ Donor to Four Transplant Recipients, New England Journal of Medicine, 2005; 352: 1103-11. Rodney E. Willoughby, Jr.... Survival after Treatment of Rabies with Induction of Coma, New England Journal of Medicine, 2005;352:2508-14. Rodney E. Willoughby, Jr.... Survival after Treatment of Rabies with Induction of Coma, New England Journal of Medicine, 2005;352:2508-14. Charles E. Rupprecht, Robert V. Gibbons, Prophylaxis Against Rabies, New England Journal of Medicine, 2004;351:2626-35. Charles E. Rupprecht, Robert V. Gibbons, Prophylaxis Against Rabies, New England Journal of Medicine, 2004;351:2626-35. 33 ـ سيماني، سوسن، بيماري هاري، در : بيماري‌هاي مهم مشترك بين انسان و حيوان در ايران، معاونت آموزشي و امور دانشجويي وزارت بهداشت، چاپ اطلاعات، سال 1384، صفحات 203-165.33 ـ سيماني، سوسن، بيماري هاري، در : بيماري‌هاي مهم مشترك بين انسان و حيوان در ايران، معاونت آموزشي و امور دانشجويي وزارت بهداشت، چاپ اطلاعات، سال 1384، صفحات 203-165.

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