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Compendium June 2012 (Vol 34, No 6)

Analgesia in Foals

by Sheilah A. Robertson, BVMS (Hons), PhD, DACVA, DECVAA, MRCVS

    Abstract

    The alleviation of pain in foals is an important welfare issue, increases patient and personnel safety, results in less disruption of homeostasis, and enhances return to normal function. It is important to anticipate and prevent noxious stimuli because pain in the neonatal period can alter pain processing, leading to altered pain thresholds and responses later in life as well as aversive behaviors. The key to assessing pain in foals is observation of behavior. Despite limited pharmacokinetic and efficacy information, understanding the unique physiology of foals and the mode of action of available drugs allows practitioners to strive to ensure the comfort of these patients.

    Despite significant advances in many areas of equine neonatology, very few studies have been published on pain assessment or efficacy of analgesics in equine neonates. The changes in physiologic variables (e.g., cardiac output, arterial blood pressure, arterial blood gas, clinical chemistry values) between birth and adulthood are well documented in foals, but changes in the somatosensory system during this period remain largely unstudied. Providing analgesia for foals undergoing painful procedures is humane, greatly improves the speed and ease of procedures, and increases patient and personnel safety. In addition, postprocedural comfort is associated with a more rapid return to normal function, less catabolism, and a more stable physiologic status, including heart rate, blood pressure, and gastrointestinal (GI) motility. Repeated painful or unpleasant experiences can cause foals to become averse to handling and human interaction, leading to behavioral problems.

    Key Points

    • Foals are neurologically mature at birth and are capable of conscious perception of pain.
    • Untreated pain in the neonatal period can alter pain processing, leading to altered pain thresholds and responses later in life.
    • Objective measures such as heart rate may not always correlate with pain and are influenced by factors such as hypovolemia, fear, stress, and medication; therefore, careful observation of behavior is critical when assessing pain in foals.
    • Pharmacokinetics in foals are often markedly different from those in adult horses because of differences in body composition, protein binding, and organ maturation. In addition, between birth and several months of age, these variables are in flux, resulting in differences between foals of different ages. For example, the pharmacokinetic parameters of butorphanol in 3- to 12-day-old foals are markedly different from those in adult horses. In contrast to adult horses—which show excitement, ataxia, and increased locomotor activity after administration of butorphanol—foals become sedate, have increased suckling activity, and do not show increased locomotor activity.

    Early Pain Experiences

    Sentience and the capacity for consciousness are prerequisites to experiencing pain.1 The stage of neurologic development at birth also dictates whether a newborn animal can experience pain. At birth, foals are considered neurologically mature and rapidly progress from electroencephalographic (EEG) shutdown to unconscious wakefulness, then conscious wakefulness. Neuroinhibition is reduced by factors such as reduced levels of adenosine, allopregnenolone, and pregnenolone due to loss of the placenta, resulting in rapid onset of consciousness after birth. In lambs, which are also considered neurologically mature at birth, EEG studies indicate that cerebral sensitivity develops rapidly over the first week of life, during which time behavioral, hormonal, and physiologic responses to painful stimuli are well documented.2 Although similar detailed studies are not available in foals, it seems likely that they are capable of suffering in the early neonatal period in response to sufficiently noxious stimuli.1

    Early pain experiences in rat pups and human neonates have far-reaching negative consequences later in life.3–6 Repeated insertion of a 25-gauge needle into the paw of rat pups from days 0 to 7 after birth resulted in decreased pain thresholds, decreased weight gain, and altered behaviors as adult rats.7 Pronounced hyperinnervation and decreased threshold to mechanical stimulation occurs following creation of skin wounds in the paws of neonatal rat pups and persists after wounds are visibly healed.8 A study by Taddio and colleagues3 compared the response to routine vaccination at 4 to 6 months of age in three groups of male infants; one group was uncircumcised, one group underwent circumcision without analgesics, and one group received local anesthesia before the procedure. Circumcised infants who did not receive analgesics showed a stronger pain response to subsequent routine vaccination than did uncircumcised infants; in the other circumcised group, preoperative analgesia attenuated the pain response to vaccination.3 Human neonates who are nursed in intensive care units have well-documented changes in pain thresholds and behavioral responses to noxious stimuli later in life.5 These studies suggest that the neonatal central nervous system is plastic and vulnerable to damage, which may be permanent.

    Many foals develop painful medical (e.g., meconium retention, gastroenteritis, infectious synovitis, flexural deformity, gastric ulceration) or surgical (e.g., colic, angular limb deformities, fractures, uroperitoneum) conditions or do not have painful conditions but are nursed in critical care units where they may be subjected to painful diagnostics (e.g., abdominocentesis) or nursing procedures (e.g., venipuncture; arteriopuncture; placement of intravenous catheters, nasogastric tubes, or urinary catheters). Thus, clinicians should proactively anticipate, prevent, and alleviate painful conditions and procedures to the greatest extent possible.

    Assessing Pain in Foals

    To claim that pain has been treated effectively implies that the pain can be recognized and measured. In the clinical setting, clinicians rely on objective (e.g., heart rate) and behavioral assessments of pain. In adult horses, heart rate may be related to pain but can be affected by other variables, such as fear, excitement, hypovolemia, and drugs (e.g., α2-adrenergic agonists). Price et al9 found no difference in heart rate between horses that had undergone arthroscopic surgery and a control group of pain-free horses, although clear differences in behavior were identified in the two groups. In a synovitis model, heart rate was only moderately specific for pain.10 Therefore, analysis of behaviors (loss of normal behaviors and/or the development of new behaviors) becomes the key to assessing pain. As stated by Ashley et al,11 “understanding the subtleties of equine communication and the behavioral repertoire of pain expression” is key to improving current pain management techniques.

    Constructing and validating pain scales for foals is challenging because the scales must be sensitive, allow minimal interobserver variability, and be easy and quick to use in practice. In addition, because horses are a prey species, their behaviors may differ depending on whether people are present or observation is by video only. In adult horses and foals, some signs of pain are obvious, such as signs of severe and acute abdominal pain (FIGURE 1) . However, based on experience with adult horses, signs of pain are often subtle or easily missed if observation is only cursory. In adult horses evaluated before and after painful procedures, those considered uncomfortable spent less time eating, spent less time at the front of the stall, were less active, displayed abnormal postures, shifted their weight, and spent more time with their head held below the withers and their ears turned backward.9,12 Overt pain behaviors such as rolling, kicking, and pawing were uncommon.

    Because detailed ethograms of foals with painful conditions are not currently available, one pain-management approach is to treat these patients until normal behaviors are restored. This can be done with the help of caregivers and owners who have knowledge of the patient’s behavior before illness or surgery. Because the stress caused by maternal separation may result in behaviors that could be confused with pain, foals should be treated and evaluated in the presence of the dam when possible. It is likely that many pain behaviors in foals, especially if they are weak and compromised, are subtle and easily overlooked. Therefore, it should be assumed that conditions or procedures known to be painful in adult horses or neonates of other species require analgesia. No foal should have to “earn” analgesia.

    Drug Disposition and Metabolism in Foals

    For many drugs, disposition in foals is different than in adult horses, so dosage changes may be needed to avoid subtherapeutic or toxic concentrations. Pharmacokinetics are influenced by body composition and organ maturation, especially hepatic and renal function. Marked pharmacokinetic differences for several drugs have been noted in neonatal, 1-week-old, 1-month-old, and older foals. Compared with adult horses, foals have greater total body water, plasma, and extracellular fluid volumes as a percentage of their body weight.13,14 In foals up to 1 month of age, extracellular fluid accounts for 35% to 40% of body weight compared with 25% in adult horses,13 and this may influence drug uptake and distribution. The free (active) fraction of drug may be higher in foals because of decreased protein binding.15 The liver is the primary site of drug metabolism, so having data on age-related hepatic function is important for choosing appropriate drugs. The pharmacokinetics of chloramphenicol during the first week of life suggest that glucuronide synthesis matures rapidly16 in healthy foals; therefore, metabolism of morphine should be possible. In one study,15 the hepatic oxidative capacity for diazepam was low at 4 days but reached an adult horse level after 21 days of age; therefore, accumulation is possible after repeated dosing in foals younger than 3 weeks. Renal function is an important determinant of the excretion of many drugs. Foal kidneys appear to be functionally mature; foal urine is dilute, but rates of excretion and clearance of electrolytes in foals are similar to or higher than those in adult horses.17 The glomerular filtration rate and effective renal plasma flow from 1 to 10 days of age are not significantly different from those of adult horses.17,18 However, even in healthy foals, clearance and excretion of drugs may differ from adults (see NSAIDs section below). Hypoxemia and azotemia can markedly alter excretion, so the dosage of renally excreted drugs may require adjustment in compromised foals. An additional factor to consider, especially when drugs that act on the central nervous system (e.g., opioids) are used, is the permeability of the blood-brain barrier.19,20 Age-related changes in blood-brain barrier permeability have been reported in some species,20 but much less is known about this in foals. Because many of the factors described above have opposing effects and are in transition during the neonatal period, the patient’s response to a drug is unpredictable.

    Analgesics

    The major classes of analgesics are opioids, NSAIDs, local anesthetics, and α2-adrenergic agonists (TABLE 1) . Although there is information on the pharmacokinetics of a few analgesics in foals, there is little information on the pharmacodynamics of these drugs. In addition, the lack of validated pain scoring systems for foals renders pain management empirical in this population. However, by using available information, including the factors that influence drug action, and by paying close attention to clinical and behavioral signs, clinicians can provide pain relief to foals.

    Opioids

    Pharmacokinetic data on foals are available for the agonist-antagonist opioid butorphanol, which has been widely used in equine practice. In healthy 3- to 12-day-old foals, 0.05 mg/kg IV or IM had minimal effects on heart and respiratory rates, increased rectal temperature, and decreased the GI motility score without obvious adverse effects.21 Unlike adult horses, these foals became sedate and showed no increase in locomotor activity after treatment. The foals also showed a marked increase in nursing behavior, which may prove to be a beneficial drug effect. Clearance of butorphanol is faster and systemic uptake greater in foals compared with adult horses, suggesting that higher doses may be required in foals. Plasma concentrations associated with analgesia in adults were not achieved with a dose of 0.05 mg/kg in foals.21 Recent studies using a thermal nociceptive model in pony foals aged 1 to 2 and 4 to 8 weeks showed that 0.10 mg/kg IV of butorphanol provided analgesia for up to 150 minutes. A dose of 0.05 mg/kg IV did not produce significant antinociception in either age group.22

    Systemic morphine and fentanyl have been given to foals at doses similar to those used in adult horses, but little is known about the pharmacokinetics or pharmacodynamics of these drugs. Pharmacokinetic data for transdermal fentanyl are available: in 4- to 8-day-old foals, fentanyl was detected in plasma as early as 20 minutes after application of a 100 µg/h patch,23 but there was wide individual variation in peak plasma concentration (Cmax; 0.1 to 28.7 ng/mL) and the time required to reach it (Tmax; 14.3 ± 7.6 hours [standard deviation]). Rectal temperature rose above 38.5°C (101.3°F) in all foals, but the authors stated that the patch was well tolerated and there was no change in fecal production, urination, or activity related to the patch. Further studies are needed to fully evaluate the role of systemic opioids for pain management in equine neonates.

    Many foals are affected by septic arthritis/infective synovitis in single or multiple joints that require lavage, often repeatedly. Equine synovial membrane contains opioid receptors,24 and recent studies using an experimentally induced synovitis model in adult horses showed that intraarticular morphine (0.05 mg/kg) provides analgesia, remains in the joint for at least 24 hours, has antiinflammatory properties,25–27 and is more effective in duration and intensity of effect than local anesthetics in the presence of synovitis.28 This simple technique could provide pain relief with minimal adverse effects in foals with septic joints. Further study is warranted.

    NSAIDs

    Pharmacokinetic studies on the use of NSAIDs in foals have included phenylbutazone,29 ibuprofen,30ketoprofen,31 and flunixin meglumine.32,33 Many of these studies were primarily aimed at the use of these drugs for their antiendotoxin rather than their analgesic effects. There were differences in volume of distribution, half-life, and clearance for phenylbutazone (2.2 mg/kg IV) between foals and adult horses, with foals younger than 24 hours showing a reduced ability to eliminate the drug.29 Potential adverse effects of these drugs include GI ulceration, nephrotoxicity, and platelet dysfunction. High doses (5 mg/kg bid for 7 days) of phenylbutazone did not produce clinical signs of renal or GI disease or changes in complete blood counts or blood chemistry profiles in healthy 7- to 10-day-old foals, but renal changes could be detected by ultrasonography (premortem), and gastric ulcers and histologic changes in the kidneys were found at necropsy.34 In healthy 5- to 10-week-old foals, ibuprofen at doses up to 25 mg/kg tid for 6 days produced no adverse effects, but the authors cautioned that this may not be true in foals when renal function is compromised.30 In healthy 1-day-old foals, a single dose of ketoprofen had to be increased to 1.5 times the adult equine dose of 2.2 mg/kg to achieve a therapeutic plasma concentration.31 However, because of reduced elimination, these authors stated that dosing intervals may need to be lengthened to avoid toxicity and that dosing should be based on clinical response.31 It is also suggested to increase the dose of flunixin by up to 1.5 times the adult dose in 1-day-old foals; as with ketoprofen, the dosing interval should be longer as well as based on clinical response.32 However, when treating septic or dehydrated foals, NSAIDs must be used cautiously. The pharmacokinetics of flunixin meglumine (1.1 mg/kg IV) are different in foals at 1, 10 to 11, and 27 to 28 days of age.33 Drug elimination was significantly decreased in the youngest foals, most likely because of decreased hepatic metabolism and renal clearance. Despite these differences, doses up to 2.2 mg/kg for 5 days in 2-day-old, healthy Belgian-cross foals caused no clinical, blood cell count, blood chemistry, or pathologic changes.35 However, doses of 6.6 mg/kg resulted in GI ulceration.35 These studies suggest that the use of NSAIDs to treat acute perioperative or traumatic pain in young foals should be safe and effective, but NSAIDs should be used judiciously in compromised or critically ill foals. NSAIDs should be used cautiously in hypovolemic foals, as the combined effects of decreased gastric perfusion and NSAIDs could more easily result in gastric ulceration and/or renal compromise. If analgesia is required in these cases, butorphanol may be a better choice.

    Local Anesthetics

    Local anesthetics are versatile, likely underused agents with multiple applications for treating pain. Neuraxial (epidural or spinal) or peripheral nerve blocks with local anesthetics are simple to perform, provide complete analgesia with few adverse effects, and can often be repeated. It is not unusual for foals to respond to a painful stimulus more abruptly and profoundly than adult horses. Even under general anesthesia, foals may respond to an initial incision, even when the anesthetic depth appears adequate.36 Simply infiltrating the incision site with local anesthetic is an effective technique to block the initial response to surgery and continues to provide analgesia in the early postoperative period.

    Lidocaine skin patches (5% lidocaine; total dose: 700 mg; 10 × 14 cm) have been developed for treating postherpetic neuralgia in humans but are also used to relieve musculoskeletal pain. In adult horses, lidocaine was undetectable in serum samples collected for 12 hours after application of two patches to the medial side of each carpus37; these patches have potential for alleviating wound and musculoskeletal pain in foals.

    Topical application of local anesthetic creams facilitates catheter placement and venipuncture. Two products are readily available: (1) lidocaine in a liposome-encapsulated formulation and (2) a eutectic mixture of lidocaine and prilocaine. In cats, the success rate of jugular catheterization increased by more than 20% (from 38% to 60%) when the eutectic mixture was used,38 and similar protocols could be used in foals. The benefit of topical creams over subcutaneous infiltration is that the former does not disrupt local tissue and the vein is not obscured by a bleb. The time to onset of action with these products can range from 10 to 30 minutes; therefore, they may not be applicable in emergencies.

    Lidocaine jelly, which has a rapid onset of action when used on mucous membranes, is recommended for placing nasogastric tubes, nasal oxygen cannulae, and urinary catheters.

    Epidural Anesthesia

    Exploratory laparotomy may be required in foals during the first month of life, but the mortality rate related to general anesthesia (regardless of health status) in these foals is higher than in adult horses.39 Therefore, alternative techniques should be explored. With the advent of laparoscopic surgery, it may be possible to perform abdominal procedures in conscious foals. With this in mind, Lansdowne et al40 studied the cranial spread of various volumes of methylene blue (by postmortem examination) and the analgesic effects of mepivacaine (by response to an electrical stimulus while under isoflurane anesthesia) in the epidural space of foals. A volume of 0.2 mL/kg of 2% isotonic mepivacaine produced analgesia up to the caudal thoracic dermatome, which would allow caudal procedures to be performed; studies using different volumes of injectant and different combinations of drugs should help find the best technique for epidural analgesia in foals.

    Epidural administration of detomidine and morphine significantly reduces experimentally induced hindlimb lameness in adult horses.41 Doses of 0.1 to 0.2 mg/kg of morphine and 10 to 30 μg/kg of detomidine are very effective and can last up to 12 hours. I have used similar combinations in foals with hindlimb pain due to fractures and infections. However, detomidine produces obvious adverse systemic effects, including sedation and cardiovascular depression41; in addition, detomidine is associated with a high incidence of arrhythmias (see the α2-Adrenergic Agonists section below) in foals. Therefore, xylazine, which has fewer adverse cardiopulmonary effects in foals and does not appear to be extensively absorbed systemically, would be a good choice for epidural administration and can be used at doses similar to those recommended for adult horses (0.25 mg/kg).42 Epidural drugs may be given by epidural injection or, if long-term treatment is anticipated, an epidural catheter. Local inflammation and fibrosis, but without obvious adverse systemic effects, have been reported after long-term (14 days) epidural catheter placement in adult horses.43 Therefore, the pros and cons of this technique should be carefully considered. Ideally, preservative-free drugs should be used for repeated administration; however, of the drugs discussed, only morphine is available in a preservative-free formulation.

    Systemic Lidocaine Infusion

    Systemic lidocaine infusions are widely used in equine medicine. The beneficial effects of lidocaine may be a result of its antiinflammatory, prokinetic, or analgesic actions. Cook and Blikslager44 made a strong argument that the antiinflammatory properties of lidocaine benefit horses with ileus. Murrell et al45 used EEG changes as an objective measure of nociception in anesthetized ponies undergoing castration and showed that intravenous lidocaine infusions obtunded the castration-associated EEG changes, supporting the antinociceptive effects of lidocaine. Intra- and postoperative lidocaine had beneficial effects on peritoneal fluid accumulation and jejunal distention46 and reduced the incidence of postoperative ileus by approximately 50% in one study47 and decreased the volume and duration of reflux compared with the use of saline in another study.48 In adult horses, loading doses of lidocaine vary from 1.3 to 5.0 mg/kg, and infusion rates vary from 25 to 100 mg/kg/min. However, pharmacokinetic variables are altered by disease, concurrent medication, and decreased cardiac output, which occurs with general anesthesia and in compromised patients and could result in toxicosis, which is well-described in adult horses.49 Ceftiofur sodium and flunixin meglumine decrease the protein binding of lidocaine, and lower infusion rates of lidocaine should be used in patients receiving concomitant drugs that are highly protein bound.50 The pharmacokinetics of lidocaine in foals of varying ages have not been reported, and toxic doses have not been established. Lidocaine infusions could be beneficial for foals with painful abdominal disease. However, until more information is available, the lower loading doses and infusion rates are recommended.

    α2-Adrenergic Agonists

    α2-Adrenergic agonists produce sedation, muscle relaxation, and analgesia. Xylazine and romifidine are excellent choices for use in healthy foals because they produce fewer cardiopulmonary changes than detomidine51 and can be used as premedication and for short invasive procedures such as passage of a nasogastric tube. Xylazine or romifidine can be used in combination with butorphanol to provide additional analgesia; in my experience, these combinations result in a more cooperative foal. However, it is important to note that the duration of analgesia achieved with α2-adrenergic agonists is shorter than the sedation they provide; plasma levels associated with sedation are much lower than those needed to produce analgesia.52,53

    Other Analgesics

    The analgesic effects of subanesthetic doses of ketamine are documented in humans and some other species, and a summary of the actions and effects of ketamine in horses suggests that it should be explored as a treatment option.54 If ketamine has analgesic actions in foals, it could be an important component of pain management protocols, especially in compromised animals, because of its sympathomimetic actions.

    Multimodal Analgesia

    Combining two or more drugs from different categories with different modes of action intuitively makes sense for providing more robust analgesia and for decreasing adverse effects by using lower doses of each drug. Although multimodal analgesia has not been well documented in foals, in a small clinical study of adult horses, transdermal fentanyl combined with an NSAID seemed to be effective in patients when pain did not respond to NSAIDs alone.55

    Future Directions

    Although analgesics are being used in foals, many of the dosages are empirical, and the lack of validated pain scoring systems for foals precludes the performance of multicenter efficacy trials. Pharmacokinetic and pharmacodynamic studies and the development of validated pain evaluation tools should be priorities for equine neonatologists. In addition to increasing knowledge of the use of analgesics in foals, reducing surgical trauma by using minimally invasive techniques such as laparoscopy and thoracoscopy should be encouraged.

    Examples of Clinical Protocols

    Case 1: A 3-day-old foal with multiple septic joints is scheduled for joint lavage (FIGURE 2) .

    If multiple joint lavages may be required, an intravenous catheter should be placed to avoid multiple venipunctures. Intravenous access also avoids the need for repeated intramuscular injections for long-term antimicrobial therapy. Before placement of an indwelling catheter, the hair should be clipped over the jugular vein and the area should be aseptically prepared. A topical local anesthetic should be applied and temporarily covered with an occlusive dressing until the drug has taken effect (~10 minutes when using liposome-encapsulated lidocaine; up to 30 minutes when using the eutectic mixture of prilocaine and lidocaine). This greatly enhances catheter placement, making future treatments simple and quicker. However, it is not always practical to wait this long; therefore, subcutaneous infiltration of lidocaine or mepivacaine using a small needle (25 to 27 gauge) is a suitable alternative, and desensitization occurs rapidly. The foal could be premedicated with intravenous diazepam (0.1 to 0.2 mg/kg) and butorphanol (0.10 mg/kg) and anesthesia induced with ketamine (2.0 to 2.2 mg/kg) or propofol (1 to 4 mg/kg given slowly to effect). Depending on how long the procedure will take, this may be sufficient anesthesia. If a longer period of anesthesia is needed, ketamine or propofol can be repeated, or isoflurane can be administered by face mask or after intubation. After flushing has been completed, morphine can be placed in the joint. In addition, systemic NSAIDs can be very effective for this type of inflammatory pain but should be used judiciously in neonates.

    Case 2: A 1-month-old foal is scheduled for surgical correction of a carpal valgus deformity of the left limb.

    In many cases, this is a short procedure and could be accomplished using injectable anesthesia alone. An appropriate injectable regimen for this foal would include xylazine (0.5 to 1.0 mg/kg IV) and butorphanol (0.10 mg/kg IV) followed by ketamine (2.0 mg/kg IV). After preparation of the surgical site, local infiltration at the surgical site obtunds the response to the initial incision, decreasing the need for additional injectable anesthesia. NSAIDs would be beneficial and should be needed for only a few days.

    Case 3: An 8-week-old miniature foal has a fractured femur (FIGURE 3) .

    This foal requires placement of an intravenous catheter (as described in Case 1) for administering anesthesia and perioperative analgesics, fluids, and antimicrobials. Xylazine (0.25 to 0.50 mg/kg) and butorphanol (0.10 mg/kg) would be effective premedications. The foal should be fully supported before administration of these drugs to prevent collapse due to muscle relaxation, which could further damage the femur. After intubation, anesthesia could be maintained with isoflurane or sevoflurane. To provide intraoperative analgesia, the following techniques could be considered:

    • Constant-rate infusion of butorphanol (20 to 25 µg/kg/h)
    • Epidural administration of a local anesthetic and morphine

    Both techniques produce an anesthetic-sparing effect so that lower inspired concentrations of an inhalant agent can be used, thereby improving the foal’s cardiopulmonary function. The butorphanol infusion could be continued into the recovery period and adjusted based on clinical assessment of the foal’s behavior. If the epidural route was used, morphine may provide up to 12 hours of postoperative analgesia. NSAIDs would be an important component of a multimodal pain management protocol for this foal and can be started before surgery and continued for up to several weeks afterward, with monitoring for adverse effects such as gastric ulceration, gastroduodenal ulcer disease, renal dysfunction, and right dorsal colitis. Intermittent icing of the wound to reduce swelling and pain could be beneficial in this case.

    Downloadable PDF

    Dr. Robertson is now affiliated with the American Veterinary Medical Association instead of the University of Florida. She discloses that she has received honoraria from Novartis Animal Health, Boehringer Ingelheim, and Orion Pharma.

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    References »

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