4
Biosecurity

Biosecurity, for the purposes of this report, is defined as the policies and measures taken to minimize the risk of introducing an infectious pathogen into the human, agricultural animal, and research animal populations. Animals have long been recognized as hosts of zoonoses (infectious diseases that can be transmitted to humans or other species of animals). Biosecurity should be a consideration when transporting research animals because of the close contact that can occur between research animals and human handlers or other transported animals. This creates the potential for unintentional or intentional transmission of a zoonosis into the human or agricultural animal populations. Many zoonoses, including potential (agro)bioterrorism agents, are difficult to detect in an infected animal because they cause asymptomatic disease in the host species. However, the effect of zoonoses can be significant in humans and agricultural animals, causing severe disability or death and negatively affecting the capacity of the agricultural sector.

Another biosecurity concern is transmission of an infectious pathogen to a research animal during transportation and introduction of the pathogen into the colony that receives the animal. Infectious pathogens can negatively affect the health of the research animal and colonies, confounding research utilizing the infected animals.



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4 Biosecurity B iosecurity, for the purposes of this report, is defined as the policies and measures taken to minimize the risk of introducing an infec- tious pathogen into the human, agricultural animal, and research animal populations. Animals have long been recognized as hosts of zoonoses (infectious diseases that can be transmitted to humans or other species of animals). Biosecurity should be a consideration when trans- porting research animals because of the close contact that can occur between research animals and human handlers or other transported animals. This creates the potential for unintentional or intentional trans- mission of a zoonosis into the human or agricultural animal populations. Many zoonoses, including potential (agro)bioterrorism agents, are diffi- cult to detect in an infected animal because they cause asymptomatic disease in the host species. However, the effect of zoonoses can be signifi- cant in humans and agricultural animals, causing severe disability or death and negatively affecting the capacity of the agricultural sector. Another biosecurity concern is transmission of an infectious patho- gen to a research animal during transportation and introduction of the pathogen into the colony that receives the animal. Infectious pathogens can negatively affect the health of the research animal and colonies, con- founding research utilizing the infected animals. 65

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66 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS PROTECTING PUBLIC HEALTH AND AGRICULTURAL RESOURCES Minimizing Risks Associated with Transporting Research Animals with Experimentally Introduced Zoonoses Increased efforts to improve the biosecurity of human populations and the agricultural sector have resulted from passage of the USA Patriot Act (2001), the Bioterrorism Preparedness and Response Act (2002), and enforcement of three parts of the Code of Federal Regulations (42 CFR 73, 7 CFR 331, and 9 CFR 121). These regulations establish lists of agents and toxins that have been deemed threats to humans, animals, and plants (see Table 4-1). The regulations require research laboratories that possesses any of the aforementioned agents to register its facility with the Centers for Disease Control and Prevention (CDC), designate a responsible offi- cial, perform background checks of persons who have access to the agents (conducted by the Department of Justice), and have a security plan for containment of the infectious agent. When infected animals must be trans- ported, a plan for secure transportation must be in place. That plan would normally require: • close communication between shipper and recipient; • presence of responsible officials at the originating and receiving institutions; • transfer of health records and assurances; • identification of a carrier registered by the US Department of Agriculture; • documentation of safety and security training of animal care personnel; • notification of the appropriate institutional or CDC officials in case of emergency, loss, or theft; • existence of emergency procedures (see Table 4-2); and • good record maintenance. Institutions are also required to have the appropriate level of labora- tory biocontainment as outlined by CDC and the National Institutes of Health in the Biosafety in Microbial and Biomedical Laboratories Manual (BMBL). Although many shippers meet some of the requirements for labo- ratory biocontainment, not all meet all of the requirements, the result of which is a lack of uniformity in biosecurity during transportation. The characteristics of a good shipper are outlined in Table 4-3. Further, bio- containment requirements for transportation of infected animals (Appen- dix C, BMBL) are not as clearly defined as laboratory biocontainment

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67 BIOSECURITY TABLE 4-1 Agents and Toxins That Require Registration of the Facility with CDC Bacteria Viruses (continued) Bacillus anthracis Cercopithecine herpesvirus 1 (Herpes B Botulinum neurotoxin producing species of virus) Clostridium Classical swine fever virus Brucella abortus, Brucella melitensis, Brucella Crimean-Congo haemorrhagic fever virus suis Eastern Equine encephalitis virus Burkholderia mallei, Burkholderia pseudomallei Ebola virus Cowdria ruminantium (Heartwater) Foot-and-mouth disease virus Coxiella burnetii Goat pox virus Francisella tularensis Hendra virus Mycoplasma capricolum/M.F38/M. mucoides Influenza virus (reconstructed replication capri(contagious caprine pleuropneumonia), competent forms of the 1918 pandemic Mycoplasma mycoides mycoides influenza virus containing any portion (contagious bovine pleuropneumonia) of the coding regions of all eight gene Rickettsia prowazekii, Rickettsia rickettsii segments) Yersinia pestis Japanese encephalitis virus Lassa virus Lumpy skin disease virus Fungi Coccidioides immitis, Coccidioides posadasii Malignant catarrhal fever virus (Alcelaphine herpesvirus type 1) Marburg virus Toxins Abrin Menangle virus Botulinum neurotoxins Monkeypox virus Clostridium perfringens epsilon toxin Newcastle disease virus (velogenic) Conotoxins Nipah virus Diacetoxyscirpenol Peste des petits ruminants virus Ricin Rift Valley fever virus Saxitoxin Rinderpest virus Shigatoxin and Shiga-like ribosome Sheep pox virus inactivating proteins South American haemorrhagic fever Staphlococcal enterotoxins viruses (Junin, Machupo, Sabia, Flexal, Tetrodotoxin Guanarito) T-2 toxin Swine vesicular disease virus Tick-borne encephalitis (flavi) viruses (Central European tick-born Prions Bovine spongiform encephalopathy agent encephalitis, Far Eastern tick-borne encephalitis [Russian spring and summer encephalitis], Kyasanur Forest Viruses African horse sickness virus disease, Omsk hemorrhagic fever) African swine fever virus Variola major virus (Smallpox virus) Akabane virus Variola minor virus (Alastrim) Avian influenza virus (highly pathogenic) Venezuelan equine encephalitis virus Bluetongue virus (exotic) Vesicular stomatis viruses (exotic) Camel pox virus

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68 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS TABLE 4-2 Elements of an Emergency Plan • Containers must be labeled clearly with the appropriate biohazard labels and identification of contents to inform transportation workers of package contents. • Package documentation must identify potential biohazards in the package and 24-hr contact information for a responsible official from the consignor institution. • The responsible official must be knowledgeable about the contents of the shipment and the potential hazards that it may pose and monitor the shipment in transit until receipt and confirmation by the consignee. • The responsible official will assist in the coordination of responses of emergency officials or transportation-worker safety officers in case of accident or theft. TABLE 4-3 Characteristics of a Good Shippera A good shipper of research animals: • finalizes the method of shipment, route, and special care required for a shipment before accepting it; • obtains all required federal, state, and regulatory-agency permits and documents; • ensures that the carrier is US Department of Agriculture (USDA)-certified for live-animal shipments or meets International Air Transport Association (IATA) and Department of Transportation (DOT) regulations for dangerous goods; • provides the carrier with information about the shipment, including type of animal (scientific and common name), sex, physical conditions, number of animals per container, medication given, and whether the shipment is a dangerous good; • provides containers that adhere to current IATA regulations for live animals or dangerous goods; • provides suitable bedding and food for the animals; • obtains all documentation and correct information required by IATA, by national and carrier regulations, and for the shipper’s certification; • provides special feeding and watering instructions on the outside of each container and provides the carrier with a respective copy; • develops an emergency plan and a 24-hr contact number for a responsible official to coordinate responses; and • maintains records for each shipment—including such information as the species and number of animals, dates of shipment and receipt, carrier, and name and address of consignee—for at least 3 years. aAdapted from Section 1.2 of the Live Animals Regulations (IATA, 2005). requirements. However, Appendix C of the BMBL, as well as Chapter 2 of this report, contains comprehensive information on which agencies must be contacted when transporting animals with human and agricultural animal zoonoses and can provide assistance in development of appro- priate biocontainment plans for transportation.

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69 BIOSECURITY Minimizing Risks Associated with Transporting Research Animals with Unknown Zoonoses Though research animals may be experimentally infected with agents, many zoonoses of concern are endemic in research animals or may be naturally acquired. A list of zoonotic diseases communicable from research animals to humans is presented in Table 4-4. Because many of those zoonoses cause asymptomatic disease in animals, it may not be apparent that the animal is infected. The challenge is to identify the zoonoses that animals potentially harbor, consider the likelihood that the animal is a carrier and potential for exposure, evaluate the likely severity of an adverse event, and take steps to mitigate the risk. TABLE 4-4 Examples of Zoonotic Diseases Transmissible from Research Animals to Humans Disease Potential Animal Vectors Potential Route of Transmission Bacterial Anthrax Contaminated herbivores Cutaneous, inhalation Brucellosis Cattle, goats, swine, dogs Inhalation, ingestion, direct contact Leptospirosis Cattle, dogs, horses, swine, Inhalation of contaminated rodents, reptiles, amphibians fluids, direct contact Salmonellosis Birds, swine, reptiles, turtles, Direct contact, fecal-oral tortoises Tuberculosis Domestic and wild animals Droplets Q fever Cattle, sheep, goats Inhalation, direct contact with infected animals, their birth products, or infected materials such as bedding Viral Influenza Birds, horses, swine Aerosol, physical contact Hantaviruses Rodents Aerosol, direct contact with mucous membranes, animal bites Ebola Unknown Direct contact with infected materials, possibly droplets Monkey B virus Old World monkeys Animal bites, direct contact with mucus membranes Monkeypox Ground squirrels, gambian rats Droplets Rabies Dogs, cats, wild carnivores, Animal bite, possibly airborne bats, foxes, raccoons Fungal Ringworm Bovine, birds Direct contact

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70 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS There are reports of zoonotic disease transmission from pet hamsters, rabbits, and rodents to humans (CDC, 2001, 2005a, 2005b). Since com- panion animals are often transported in unfiltered containers and are transported along with research animals (particularly during air trans- port), the potential for cross contamination during transport must also be considered. In general, contact between animals and people during transporta- tion should be restricted to prevent exposure to or transfer of zoonoses. When possible, human contact should be limited to trained animal handlers who are knowledgeable of good sanitation practices, biosafety and biocontainment, and precautions for protection against zoonoses. Special Considerations When Transporting Nonhuman Primates The transportation of nonhuman primates requires special consider- ation because the risk of zoonotic disease transmission is greater with non- human primates than any other species of research animal due to the close phylogenetic relationship between humans and nonhuman primates (NRC, 2003b). Macaques imported for research have been implicated in the transmission of B virus and Ebola virus to laboratory workers, both potentially fatal diseases in humans (Cohen et al., 2002; Palmer, 1987). B virus (also known as Herpesvirus simiae) is of particular concern as it is endemic in some populations of macaques and infected animals are generally asymptomatic. B virus and Ebola virus can be transmitted through aerosols, animal bites, scratches, contact with body fluids or tissue material, or equipment that has been contaminated with body fluids (NRC, 2003b). Due to the risks associated with zoonotic diseases transmitted from nonhuman primates, a common standard for personal protective equip- ment (PPE) has been established for workers who come into contact with nonhuman primates or equipment that has been exposed to nonhuman primates (NRC, 2003b). This standard recommends that dedicated clothing, gloves, and masks be utilized when in contact with nonhuman primates and that eye and face protection be mandatory for individuals who come into contact with macaques. Eye and face protection are also highly recommended for individuals who come into contact with other Old World monkeys. Ensuring public safety and maintaining public confidence in the ship- ping process should be concerns of both regulatory agencies and carriers. Public confidence is difficult to maintain when airline passengers observe transportation workers wearing PPE boarding their plane. However, the development and use of overshippers (a closed, environmentally con- trolled container into which a standard primary enclosure would be

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71 BIOSECURITY loaded in order to prevent a zoonotic exposure) would mitigate the need for some types of PPE (please refer to Chapter 5 for further discussion). Special Considerations When Transporting Specimens and Tissues Diagnostic specimens and tissues that are used for research are usu- ally isolated from animals that are suspected of having an infectious disease or that are from an endemic area, and they should be treated as potentially infectious and hazardous materials. Those materials should be handled according to guidelines in BMBL (5th edition, Section VI and Appendix C). All diagnostic and tissue samples should be packaged according to IATA regulations as dangerous goods (Chapter 2). Depend- ing on the suspect sample, it may be necessary for only persons who have IATA training to handle the sample. Access to the packages should be limited. If the sample potentially contains a select agent, both the shipper and the recipient must have all pertinent clearances and permits required by CDC and USDA and must have notified all appropriate agencies. PROTECTING THE BIOLOGICAL INTEGRITY OF RESEARCH ANIMALS AND COLONIES In recent years, greater attention has been paid to maintaining the microbial status of research animals and animal colonies. Scientists have rapidly expanded the use of immunocompromised rodents, such as nude mice and transgenic animals with immune deficits. Preventing exposure to infectious agents is necessary to maintain the health of these animals. In addition, scientists have discovered infectious agents, such as mouse and rat parvoviruses and Helicobacter species, that cause subclinical infec- tions but can significantly alter research results (Jacoby and Lindsey, 1998). A list of viral, bacterial, and parasitic organisms found in commonly used species of research animals is presented in Table 4-5. Many of these organisms can infect multiple species, increasing the potential for intra- species and interspecies disease transfer. The most common routes of disease transmission between animals are infectious aerosols, close contact, and fomite (an inanimate object, such as clothing, capable of transmitting infectious organisms) transmission. Each of these routes poses a risk during shipping; however, there are methods to prevent the transmission of diseases among research animals, including barrier containment, specific-pathogen diagnosis, disinfection of vehicles and shipping containers, use of personal protective equipment (PPE), and segregation of animals. Though research animal vendors gener- ally have well-established procedures to minimize biosecurity concerns, the typical researcher may need guidance in addressing biosecurity concerns

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72 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS TABLE 4-5 Infectious Agents and the Susceptible Species of Research Animals Mice Rats Viruses Sendai X X PVM (Pneumonia virus of mice) X X MHV (Mouse hepatitis virus) X MVM (Minute virus of mice) X GD-VII (Theiler’s murine encephalomyelitis virus strain) X REO 3 (Reovirus type 3) X X EDIM (Group A rotavirus) X Lymphocytic choriomeningitis vVirus X X Polyoma X MCMV (Murine cytomegalovirus) X Ectromelia X MPV (OPV) (Mouse parvovirus – Orphan parvovirus) X MAD (Mouse adenovirus) X X K virus X MTLV (Mouse thymic virus) X Hantavirus Adenovirus Parainfluenza Rotavirus PI-1 (Parainfluenza-1) PI-2 (Parainfluenza-2) RHD (Rabbit haemorrhagic disease) LCM (Lymphocytic choriomeningitis) H1 (Toolan’s H1 virus) X KRV (Kilham Rat virus) X SDA/RCV (Sialodacryoadentitis virus/Rat corona virus) X HANT (Hantaan) X RRV (Ross River virus) X Foamy virus Dengue Yellow fever Pox viruses Ebola SIV (Simian immunodeficiency virus) B virus Rat picornarvirus X RPV (OPV) (Rat parvo virus – Orphan parvo virus) X

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73 BIOSECURITY Guinea Pigs Gerbils Rabbits Hamsters Nonhuman Primates X X X X X X X X X X X X X X X X X X X X X X X continued

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74 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS TABLE 4-5 Continued Mice Rats Bacteria Streptococcus zooepidemicus Pasteurella multocida Pasteurella spp. Treponema cuniculi Bordetella bronchiseptica X X Citrobacter rodentium X Corynebacterium kutscheri X X Clostridium piliforme X X Salmonella spp. X X Mycoplasma pulmonis X X Streptobacillus moniliformis X X Helicobacter hepaticus X X Campylobacter spp. Yersinia spp. Mycobacterium spp. Burkholdria CAR bacillus X X Parasites Ectoparasites X X Gastrointestinal helminths X X Gastrointestinal protozoa and sporozoans X X Encephalitozoon cuniculi X X Hepatic coccidia Metazoa Intestinal coccidia Other protozoa Demodex

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75 BIOSECURITY Guinea Pigs Gerbils Rabbits Hamsters Nonhuman Primates X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

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76 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS TABLE 4-6 Recommendations for Shipment of Research Animals Between Institutions • Shipments of research animals between institutions should be coordinated between responsible persons at the sending and receiving institutions. They should ensure that all documentation is in order, including federal (CDC, USDA, and DOT), state, and local permits. • Shipments should be prepared by persons who have documented training in animal handling procedures and the proper use of PPE. • Animals should be placed in shipping containers that will provide protection to them and the receiving colony from microbial contamination. • Animals should be packaged according to regulatory-agency (IATA, USDA, and DOT) standards. • Shippers should provide documentation and assurances to recipients that the animals are healthy. If the recipient requires a more extensive health report, including testing for specific pathogens, the costs of the diagnostic tests should be covered by the consignee. • Only USDA-certified carriers should be used for transportation of research animals. • On receipt, the consignee should place the research animals at the appropriate level of biocontainment and quarantine before introduction into the laboratory colony. when shipping animals to a colleague. Recommendations for shipment of animals between research institutions can be found in Table 4-6. Barrier Containment Most small-animal vendors have designed shipping containers that incorporate spun polypropylene filters to provide a physical barrier to the transfer of microbial contaminants into or out of each container, thus pro- tecting research animals, colonies, and animal handlers from pathogen exposure during transportation. For gnotobiotic animals (animals whose microfauna and microflora are known in their entirety) and immuno- compromised animals, microisolation shipping containers are also avail- able. Although the sturdy construction of the vendor containers may tempt researchers to reuse them to transfer research animals to other researchers, this practice is not recommended. Most vendors sterilize or disinfect the animal containers, food, and water before loading animals. Once a container has been opened at the recipient’s facility, its sterility has been compromised. Some facilities autoclave shipping containers for reuse; however, this may increase the air resistance of the polypropylene filters, restricting air flow (White, 2004). Until it can be established that autoclaving does not restrict air flow below acceptable levels, the com- mittee suggests that the prudent course of action is to avoid autoclaving shipping containers for reuse. To ensure the biosafety of their animals,

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77 BIOSECURITY individual researchers who wish to transfer animals to other researchers should purchase presterilized shipping containers from animal vendors. Specific Pathogen Diagnosis Normally, when major vendors communicate with clients, they iden- tify the pathogens for which their animals have been tested to assure recipients that the animals sent to them are free of pathogens that could disrupt their colonies or experiments (for example, introduction of a respiratory infection would disrupt and invalidate an experiment on respiration). People shipping a few animals to colleagues do not always know the pathogen status of their animals and therefore cannot assure colony supervisors that the imported animals can be introduced safely into their colonies. To avoid inadvertent introductions of diseases, some colony supervisors quarantine incoming animals until they can gather the data required to ensure the health and safety of incoming animals (Otto and Tolwani, 2002). If facilities do not have the space and testing facilities required for that precaution, then it may be necessary for testing to be conducted at the institution of origin. Unfortunately, testing in such instances does not monitor for disease transmission during transport. Arrangements for testing and provision of assurances before introduction of shipped animals into a new colony require communication between responsible and knowledgeable officials of the institutions involved. Such officials can help to arrange safe and secure shipment of animals and arrange for the most efficient assurance of colony security. Disinfection Transportation protocols should have standardized procedures for disinfection of animal cages, transportation vehicles, and holding areas that conform to IATA, USDA, DOT, and CDC standards. Disinfection pre- vents transmission of pathogens from one shipment of animals to the next shipment transported in the same vehicle. Bedding, food, and water may be sterilized by autoclaving or gamma irradiation before and after ship- ment to prevent contamination of research animals and the receiving colony. Disinfection by sterilization or irradiation is not feasible for such items as transfer-vehicle cargo holds, large cages, and transportation- company holding areas. In these cases, however, chemical disinfection should be conducted after each transfer event. To ensure maximal effi- ciency of the disinfection process, disinfection should be applied using concentrations of chemical disinfectants and application times should be optimized according to manufacturers’ instructions.

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78 GUIDELINES FOR THE HUMANE TRANSPORTATION OF RESEARCH ANIMALS Disinfection of the outside of the shipping containers should also be considered. As discussed above, companion animals are often transported in unfiltered containers and may be transported along with research animals. Therefore, the potential for cross contamination of shipping con- tainers is present and must be considered. Another situation that may result in cross contamination is the entry of wild mice infected with lymphocytic choriomeningitis virus or mouse hepatitis virus into an animal holding area along the transportation route, such as an airport or cargo transfer station. The infected wild mouse can shed virus, thus contaminating the outside of the shipping container. Transmission of pathogens to research animals or colonies can then occur if the container is brought into a facility or animals are removed from the container with- out disinfection of the outside surfaces. Since such infections occur during transportation, diagnostic testing by the source provider does not ensure the biosecurity of either the animals or the receiving colony. Personal Protective Equipment The appropriate use of PPE can also protect research animals from human pathogens and cross contamination from other animals. For example, macaques are susceptible to human infections such as measles and tuberculosis. The use of PPE will not only prevent the transmission of B virus from a macaque to a human, but also can prevent the inadvertent transmission of measles or tuberculosis to the macaque. People who handle animals should cover their street clothing and exposed body sur- faces with PPE to reduce the risk of pathogen introduction through direct contact or aerosol. In some instances, it may be appropriate to provide handlers with a shower-based entry system. The appropriate disposal of PPE is also necessary so that the PPE does not act as a fomite for transmit- ting pathogens. For example, if PPE is worn while disinfecting incoming shipping containers, the PPE should be disposed of before moving on to other tasks. Segregation of Animals Separation of different shipments of animals is also a method for pre- venting intra- and interspecies transmission of pathogens presented in Table 4-4. The committee suggests close adherence to the recommenda- tions in the LARs regarding segregation of species and separation of animals of the same species of different origins (LARs Sections 5.3 and 10.3.2). Briefly, these regulations state that:

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79 BIOSECURITY 1. animals in quarantine must be segregated from those which are not; 2. animals known to be for laboratory use must not be stored adja- cent to other animals in order to reduce any risk of cross-infection or contamination; 3. nonhuman primates from different continents must be isolated from each other in aircraft holds, airport cargo warehouses, animal hold- ing facilities, and during all phases of ground transportation; and 4. animals that are natural enemies, e.g., cats and dogs, may be loaded in the same hold provided they are not in sight of one another. Situations in which some aspects of these recommendations are not feasible may arise. For example, an airport may not have containment facilities to separate nonhuman primate species. In these cases, other measures must be employed to prevent disease transmission. An effective means of overcoming this problem would be the development of self- contained overshippers, as recommended in Chapter 5.

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