Post-weaning multisystemic wasting syndrome (PMWS) is a globally emergent epizootic disease of swine. As the name suggests, the disease is mainly described in pigs aged 6-12 weeks and is manifest clinically by mortality, ill-thrift (wasting), paleness, dyspnoea, intermittent diarrhoea and visibly enlarged lymph nodes. Since its first description in Western Canada [1] in 1991 the disease has rapidly spread to all the major pig producing countries of the world including Europe, the Americas and Asia [2]. Most recently, the disease been reported in several countries that were previously considered free from disease (New Zealand [3] and Sweden [4]). PMWS is one of the most common forms of porcine circovirus associated disease (PCVD) on a global scale. The role of porcine circovirus type 2 (PCV2) in PMWS is clear in terms of its association with the pathology, but less clear in terms of the mechanisms of disease induction and pathogenesis. There is evidence that PCV2 was circulating, at least in Europe, as far back as the 1960s in the absence of epizootic PMWS [5]. PCV2 has been associated with a number of non-PMWS disease conditions, or PCVDs, including porcine respiratory disease complex, porcine dermatitis and nephropathy syndrome (PDNS), granulomatous enteritis, and occasional reproductive disorders [6].

The disease has had major economic, public health, and animal welfare impacts on the pig meat industry. The economic cost of PMWS across the EU is estimated at between €562-900M, extrapolated from data for the Netherlands where the disease causes a reduction in the availability of pigs for slaughter by 4% p.a. (data supplied by the MLC). Factors underlying the economic losses include fewer pigs at slaughter, reduced feed conversion rates, increased costs for management and medication of sick pigs, and costs of secondary diseases following PMWS-associated immunosuppression [7]. It was estimated in 2001 that costs on a typical UK farm were £10.39 per pig sold, or equivalent to an increase in the cost of production of £0.01 per kilogram of pig meat sold for each extra 1% mortality over previous losses (e.g. for a farm losing an extra 17% of pigs post-weaning the cost of production increases by £0.17 per kilogram) [8].

The potential impact of PMWS in terms of food safety and veterinary public health is only beginning to emerge. PMWS-associated immunosuppression may result in increased carcase contamination by food-borne pathogens (e.g. Salmonella typhimurium, Campylobacter jejuni, Yersinia enterocolitica) – arising from potentially increased prevalence of infection on-farm [7, 9] and increased shedding at slaughter. A second public health concern is an associated increase in the use of antimicrobial agents in the attempted control of PMWS-associated disease, with consequently increased potential for selecting for antimicrobial resistant bacteria and drug residues in pig meat. In the UK, where PMWS emerged between 1998 and 1999, the use of antimicrobials in pig production increased markedly from 83 tonnes/year in 1998 to 109 tonnes/year in 2001; a 31% increase despite a 7% reduction in the UK breeding pig population [10]. The introduction of PMWS is a likely driver behind this increased antibiotic use. The impact of PMWS on pig welfare is manifest through prolonged increases in mortality rates and increased numbers of ill-thriven pigs requiring hospitalization.

The clinical signs of PMWS should be considered not only at an individual pig level but also at the herd level. This is important because it allows the differentiation of the globally emergent, and economically significant, form of epizootic PMWS from sporadic, individual cases of PMWS that are believed to have been occurring prior to, and in the absence of, the epizootic disease form. Assessment of sera and tissue archives for the presence of anti-PCV2 antibodies or of PCV2 by antigen detection methods such as immunohistochemistry (IHC) and in situ hybridisation (ISH) demonstrated that PCV2 was circulating in Europe at least in the 1970s and probably earlier [5]. Furthermore, the typical diagnostic features, to be discussed later, including lymphoid tissue depletion and PCV2 detection were described in Spain in archived tissues dating back to 1986 [11]. However, the prevalence of the condition was much lower at that time, in comparison to the epizootic form of PMWS first experienced in Canada in 1991, and was presumably misdiagnosed.

Individual cases of PMWS present in pigs aged typically between 6 and 14 weeks of age. They show signs of wasting (cachexia), paleness, intermittent diarrhoea, dyspnoea, enlarged inguinal lymph nodes, and occasionally jaundice. Some artificial infection models have demonstrated PMWS in animals as young as three weeks of age, but such age groups are extremely rarely affected in field situations. Animals affected with PMWS will deteriorate rapidly over a period of 1-2 weeks. As a feature of PMWS-associated immunosuppression, they may also show signs of secondary or super-imposing viral, bacterial or fungal infections such as PRRSV, E. coli enteritis, Salmonellosis, Haemophilus parasuis (Glasser’s Disease), candidiasis, or Pneumocystis carinii [7, 12]. With segregation and careful management a proportion of affected cases may survive but a key feature of clinical PMWS is that affected animals are refractory to treatment with antimicrobials.

At the herd level an outbreak of PMWS is often presaged by a variable increase in mortality associated with pathogens already endemic to the herd, for example, Glasser’s Disease (H. parasuis), followed some weeks later by the appearance of typical clinical signs of PMWS in individual pigs. Post-weaning herd mortality will increase at this point. Mortality was found to average 18% on affected farms and remained at this level for a minimum of 3-5 months according to a recent UK-based epidemiological survey [13]. There is great variation in morbidity for PMWS (4-30%), according to the underlying health status of the affected farm, but mortality of affected animals is high (70-80%) [1, 14]. Herds affected with PMWS often, but not always, show an increased frequency of cases of PDNS. This sporadic syndrome presents with a morbidity of <1%, typically with a high fever, an extensive skin rash, and muscle stiffness [15]. At necropsy there is subcutaneous oedema, generalised haemorrhagic lymphadenopathy, and typical petechiation and swelling of the kidneys. The pathological basis is reported to be a systemic necrotising vasculitis associated with type III hypersensitivity (immune complex deposition). The aetiology of PDNS is not clear but PCV2, along with other infectious agents such as Pasteurella sp., is believed to play a significant role [15]. Affected pigs in the early stages of disease may respond to anti-inflammatory treatment but usually require culling. However, the key concern with PDNS is the difficulty it poses, at a gross individual pig level, in differentiation from Classical Swine Fever (Hog Cholera).

Porcine respiratory disease complex (PRDC) is a PCVD that occurs more frequently than PMWS in the US [16]. The disease presents as a growth check associated with pneumonia of mixed aetiology in pigs aged 16-20 weeks. Clinical signs may overlap with those for PMWS but the disease is more clearly associated with pneumonia, and occurs in older pigs, mortality rates are lower, and there is observable response to vaccination or treatment for the contributing infectious agents such as Mycoplasma hyopneumoniae, swine influenza, or porcine reproductive and respiratory syndrome virus (PRRSV) [6].

The pathology of PMWS, and the other PCVD, was recently reviewed by Segales et al (2004) and the results of a survey of 396 affected pigs is summarised in rank order of occurrence, in Table 1 [17]. At necropsy, the carcase is emaciated and pale, the most obvious features are the findings of non-collapsed, tan coloured lungs and the observation of multiple enlarged lymph nodes. On their cut surface the lymph nodes show a homogenous texture rather than the follicular structure found in normal lymph nodes. Multiple white foci are commonly seen in the kidney and gastric ulceration is often present. Other more variable findings include hepatic shrinkage or enlargement, and jaundice. Clinical and pathological evidence for congestive heart failure was found amongst PMWS-affected pigs, including ascites, pleural effusion, pulmonary oedema, and flaccid myocardium has been described [18] which might potentially be a consequence of pre- or peri-natal infection of cardiomyocytes by PCV2 [19].

Histopathological evaluation of lymphoid tissue from affected pigs reveals extensive loss of the normal follicular architecture with depletion of lymphocytes from the B and T cell regions and replacement by a homogeneous, or occasionally patchy, infiltrate of histiocytic cells intermixed with occasional multinucleate giant cells. Another key feature is the presence, within the histiocytic and giant cell populations, of large numbers of grape-like basophilic, cytoplasmic inclusion bodies. Immunohistochemical (IHC) and in situ hybridisation (ISH) studies have identified these inclusions as PCV2 [2, 20, 21]. Lesions are not always detectable in all lymph nodes in an affected pig and further, lesions may be only mild, especially in recently infected or convalescent animals. Notable histopathological changes are described in the lungs of affected pigs where a marked interstitial pneumonia with inter-alveolar lympho-histiocytic infiltrate may be observed, with variable numbers of multinucleate giant cells and macrophages present [20]. The presence of PCV2 can be demonstrated in these cells, even in the absence of inclusion bodies, by ISH ([20]. In cases of PRDC, the final histopathological picture depends upon the prevailing aetiological agents but lympho-histiocytic infiltrates throughout the lung is characteristic for PCV2 infection and fibroplastic changes are typically found in the bronchial and bronchiolar mucosa and submucosa of affected animals ([17, 22].

There is a need to differentiate between a herd diagnosis of PMWS and an individual definition of PMWS since Segales et al (2003) [23] noted that a small number of cases of PMWS can occur on farms that otherwise show good production data and low overall mortality. Similarly, diagnosis of PMWS in an individual pig from a farm experiencing increased wasting and mortality does not infer a herd diagnosis of PMWS until other potential causes of wasting (enteric diseases, viral diseases including PRRS) have been excluded.

The currently accepted approach to diagnosis of PMWS at the level of the individual pig is based upon the observations of Sorden et al (2000) and is comprised of 3 components [24], all of which must be present:

Segales attempted to provide a herd based definition of PMWS at the recent Congress of the International Pig Veterinary Society in Hamburg, 2004 [25]. In summary, at herd level, there should be:

Porcine circoviruses belong to the genus Circovirus, family Circoviridae, and represent the smallest non-enveloped, single stranded, negative sense, circular DNA viruses that replicate autonomously in mammalian cells [26]. The genus contains PCV1 and PCV2, psitaccine beak and feather disease virus, and the Columbid Circovirus of pigeons (reviewed by Mankertz 1997) [26]. Circoviruses also exist in plants, and this group was recently renamed Nanoviridae, including clover stunt virus and banana bunchy top virus [27].

Two types of PCV have been characterised, PCV1 and PCV2. Of the 6 open reading frames (ORFs) described for PCV these two viruses show 83% nucleotide homology at ORF1 but only 67% homology at ORF2 [28]. PCV1 is considered to be a non-pathogenic virus of pigs, having first been been discovered as a persistent tissue culture contaminant in pig kidney cell lines [29] and has not been associated with disease in commercial or experimental conditions. Conversely, PCV2 has been shown to be a key causal agent in PMWS. The virus has consistently been detected, on a world-wide basis, in tissues of pigs showing disease [30, 31]. Characterisation of PCV2 isolates from PMWS cases around the world, and from other PCVD, indicate a close nucleotide sequence homology (>96%) and antigenic similarities using a panel of monoclonal antibodies, indicating the possibility of a single pathotype [32]. However, minor variations in nucleotide sequence have been described, particularly in ORF2, and the significance of these variations in terms of host and tissue tropism and pathogenicity remains to be determined [33].

A number of studies have examined the necessity for permissive cofactors in the development of full PMWS since artificial infection models using PCV2 alone, with very few exceptions [34], do not reliably reproduce full clinical PMWS in all pigs although lymphoid pathology is induced [35-37]. Cofactors under consideration have included co-infections with common pig pathogens, managemental factors, vaccination strategies and, finally, co-infection by novel infectious agents.

Viral co-infections such as PPV and PRRSV were demonstrated to exacerbate disease in artificial challenge models [38, 39] and, in the case of PRRSV, in field cases [40]. The importance of immune modulation in predisposition to PMWS by, for example, the use of adjuvanted vaccines against other commercial diseases has come under close scrutiny. There is strong evidence that commercial on-farm vaccination strategies can exacerbate PMWS [41], and this been confirmed in a challenge models using immune-modulatory substances [42] and various commercial bacterins [43]. Work at Iowa Sate University has identified the significance of timing of vaccination and adjuvant type for the impact on PMWS pathology in a challenge model. Vaccinations given at least 2-4 weeks prior to PCV2 challenge appear not to impact on PMWS pathology [44], while oil in water adjuvants had a greater impact on the severity of lymphoid depletion than aqueous or aluminium hydroxide adjuvants [45].

There is a growing body of information which, taken together, indicates that a permissive cofactor supporting the global emergence of epizootic PCV2-associated PMWS might be a novel, as yet uncharacterised, infectious agent. Firstly, the disease has behaved in a typical epizootic fashion by spreading globally, step-wise, in a short period of time such that, by 2002, only a handful of countries remained free of epizootic disease. Many of the remaining unaffected countries, such as Denmark, Scotland, and New Zealand, have since shown evidence of disease. Secondly, while PCV2 is undoubtedly necessary for the full manifestation of PMWS there is evidence that PCV2 has been circulating in the global pig population for many decades in the absence of disease [5]. There is evidence that PCV2 isolates from farms, and even countries, that were unaffected by PMWS were not significantly different at a genomic level from isolates obtained from affected farms [32]. Furthermore, an archived isolate of PCV2 obtained from Sweden in 1993, prior to the country first reporting PMWS in 2003, was able to produce disease in a co-infection model suggesting that PMWS-potential was not restricted to PCV2 alone [46]. Finally, within a given country, the disease appears to spread in a geographically progressive manner that reflects transmission of an infectious agent. There is epidemiological evidence [13] that the progressive pattern of emergence of PMWS in the UK reflected the movement of a disease within an immunologically naïve population. This survey found an 83% prevalence of PMWS on 116 farms studied in the UK but all herds within the study showed evidence of exposure to PCV2, supporting the argument for an infectious but, as yet uncharacterised, cofactor.

The contributory role of managemental cofactors, such as physiological stress and general hygiene conditions, in pathogenesis of PMWS has been suspected since Madec put forward his observations on follow-up studies of diseased farms in France [47]. However, dissection of the significance of these husbandry based effects has had to await the outcome of extensive epidemiological investigations only now being published (see below).

Epidemiological studies of PMWS are an essential milestone on the route to improved methods for disease control but they have been hampered by the complex relationship between PMWS and PCV2, and the subsequent difficulty in obtaining rapid diagnosis. Seroprevalence of PCV2 in Europe is believed to be around 100%, irrespective of the presence or absence of PMWS.

Nevertheless, given the essential involvement of PCV2 in PMWS, much work has been done to understand the ecology of PCV2 within pig populations. The virus is present in pig herds of high and low general health status, and even wild boar [48]. Surveys of farrow to finish farms, detecting PCV2 by PCR, found that the prevalence of infection increased significantly at weaning, reaching a peak in excess of 65% in 3-4 month old pigs [49]. Most PCV2 infection therefore appears to occur at weaning rather than from the dam. Routes of shedding of PCV2 include respiratory droplet, faeces, and urine [50] with correlation between the level of viral shedding and the severity of PMWS associated disease. Intermittent shedding of PCV2 has been described in semen of clinically normal boars [51]. Further work is required to address the possibility, and significance, of differences in PCV2 infection dynamics in PMWS affected versus unaffected herds.

A practical study of PMWS transmission was recently undertaken which confirmed that weaner pigs taken from a PCV2 seropositive, but PMWS-negative, farm developed signs of PMWS when co-mingled with PMWS affected pigs over a 6 week period [52]. Refinement and expansion of these infection models will undoubtedly shed light on the significance of PCV2, or other pathogen, infection dynamics.

Risk factors for PMWS occurrence have been identified from cross-sectional epidemiological studies. Rose et al (2003) identified positive correlation between infections with parvovirus or PRRSV and PMWS [53]. Other positive correlations in this study included the use of large weaning pools, high levels of piglet cross-fostering, and shared under-floor slurry pits. A cross-sectional study undertaken across 116 randomly selected farms in the UK identified risk factors for disease that included purchase of gilts (in the early stages of the epizootic), herd size of >600 breeding sows, proximity to a pig grower unit, location within 5 miles of a PMWS-affected farm, and permitting access to visitors who were not 3 days pig-free [13]. This latter finding raises the potential significance of humans in transfer of disease and enforces the value of appropriate biosecurity steps in maintaining exclusion of PMWS from unaffected farms. A smaller survey in Spain identified a higher prevalence of anti-PCV2 antibody in pigs at 12 weeks of age on PMWS affected farms versus unaffected farms, indicating that earlier infection with PCV2 might be a risk factor for disease [54]. Finally, a case control study on 20 herds in the Netherlands identified concurrent infection with PRRSV as a risk factor [40], providing field support to the experimental evidence based on challenge studies described earlier [39].

Current evidence supports a central role for immune dysfunction in the pathogenesis of PMWS. Evidence to support this has been built in a number of areas. Firstly, studies of immune cell subsets in affected lymphoid tissue revealed extensive depletion of lymphocytes and follicular dendritic cells from follicular regions, together with increased numbers of histiocytic cells (MAC387 antigen positive) [55]. The causes of this lympho-depletion are not clear. Apoptotic changes do not appear to be responsible [56] but evidence has pointed towards reduced high endothelial venule expression [57] in affected tissues and possible subsequent reduced transmigration of lymphocytes form the circulation. However, the second piece of evidence for a major role of immune dysfunction in driving PMWS is that lymphopenia is also recorded in the blood circulation, as shown by reduced B and T (especially CD8+) lymphocytes [58, 59]. Increased circulating neutrophils and monocyte numbers superimpose on the lymphopaenia to generate a reversal of the expected ratio of lymphocytes:neutrophils. Infection studies have enabled better understanding of the kinetics of these events. Challenges resulting in clinical PMWS revealed that depletion of B-cells was already obvious and advanced at day 7 post PCV2 infection, although depletion of T-cells (CD3) was also beginning. By day 21 there was maximal depletion of both B and T-cell subsets with apparent total loss of NK cells [58]. The third piece of evidence for the importance of immune dysfunction in PMWS comes from the clinical observation of immunosuppression in the disease. Herds affected by PMWS show increased evidence of disease associated with opportunistic pathogens or unexpected pathogens including Pneumocystis carinii and Candida albicans [7, 12].

The mechanism for these observed changes is not clear since there is very little evidence at present to indicate that PCV2 can infect or replicate in monocyte/macrophages, dendritic cells, or lymphocytes [60]. Since PCV2 does not encode its own polymerase viral replication is dependent on host nuclear polymerases associated with the S phase of cellular replication [61]. Attempts to identify cells that support replication of PCV2 have been based upon nuclear localisation of the PCV2 replication associated protein, rep [62]. Currently, the most likely candidate cells for primary infection are those of epithelial origin, supported by the demonstration of nuclear PCV2 staining in epithelial cells of PMWS affected pigs [20] and by the ease with which PCV2 grows in the pig kidney epithelial cell line, PK15. Studies of in utero PCV2 infection demonstrate a predilection of PCV2 replication for the fetal cardiomyocytes [19]. It is hypothesised that the PCV2 antigen described in lymphoid tissue is primarily present as a result of phagocytosis. However, recent evidence has indicated that there may be localised replication in a subset of pulmonary alveolar macrophages [19], thus strengthening the possibility that a discrete subset of immune cells exists which act as a primary immune target cell for infection and subsequent immune dysfunction.

There is good evidence that PCV2 can, alone, induce much of the immune phenotype described above [37, 58]. However, the observation that the severity of disease in PCV2 challenge models infection is markedly exacerbated by external immunomodulatory factors such as adjuvant [42] and co-infections [38, 39] all support a multifactorial theory underlying the pathogenesis of PMWS.

Two studies have suggested that there are genetic components determining susceptibility or resistance to PMWS. Opriessnig et al found, using a challenge model, that Landrace pigs were relatively more susceptible to disease than Duroc or Large White [63]. A separate, field-based, study in Spain found the Pietrain breed to be most resistant to PMWS [64].

Since the first economically significant appearance of PMWS in the mid-1990s, producers and field veterinarians have been struggling to control the economic and animal welfare consequences of the disease. The development of appropriate control regimes has been made difficult by a number of factors including lack of knowledge of the full aetiology and epidemiology for clinical PMWS, absence until recently of vaccine approaches in clinical trial, under- and over-diagnosis of disease, the tendency of desperate producers to make multiple interventions at a given time. The attempted use of these control strategies is often based on anecdotal evidence, rather than case-control studies, since there has been a paucity of applied clinical research into the control of PMWS.

Strategies in use, or being developed, for the control of PMWS were reviewed by Donadeu et al (2004) and were considered to fall into 6 main areas: (i) Managemental, (ii) Nutritional, (iii) Genetic (iv) Therapeutic, (v) Immunological, and (vi) Biosecurity [65].

Management strategies to control PMWS were first proposed by Madec in 1999 as a 20-point plan enabling significant reduction in mortality on affected farms [47]. Later, due to difficulties in application on large commercial units, the principles were refined by Muirhead (2002) to ‘four golden rules’ of limiting pig-pig contact [66] (essentially the application of all-in all-out (AIAO) principles), reduction of physiological stress, good hygiene, and good nutrition. Other anecdotally successful management approaches to disease control include the introduction of batch farrowing (which assists AIAO) and partial depopulation. The latter technique was applied by removal of all pigs aged <9 months from farrow to finish herds with resulting significant reductions in mortality. One can only speculate on what the precise factors for success might be and what proportion of the benefit was due to control of intercurrent infections [65]. Finally, depopulation of affected herds and repopulation with stock from farms with absence of clinical disease (irrespective of PCV2 presence) has been attempted in Denmark [67]. At the time of their report 5 of 6 herds remained free from disease at 1 year post repopulation. The technique might, in theory, be refined by repopulating such herds with PCV2 negative animals derived by segregated early weaning [68] but, given the ubiquity of PCV2 around the world, it would appear unlikely that freedom from PCV2 infection could be maintained for long (<6 months in the limited personal experience of the author). Selection of an appropriate and effective disinfectant for environmental control of PCV2 in batch rearing systems was shown to be important, with only Virkon S (Du Pont Inc) showing acceptable virucidal activity [69].

Nutritional strategies have been based on the observation that PMWS associated mortality was significantly greater in ad libitum fed male grower pigs versus females and versus both sexes when maintained on restricted diets [65]. Claims have been made that plant-derived feed supplements may assist in controlling the disease but there is no evidence to support this. Genetic approaches to controlling PMWS have proved highly successful for many producers. This involves introduction of Pietrain breed genetics to herds, based on the observations of Lopez-Soria [64].

Therapeutic approaches have been attempted by practitioners, based on the clinical signs presented to them, and include the use of serum therapy, aspirin, and control of secondary infections. Serum therapy was found to improve survival rates on affected farms [70] and involved the collection of serum from a well-grown surviving pig on a PMWS-affected farm. The serum was administered by intraperitoneal injection to suckling pigs on the same farm. Aspirin was found to further reduce mortality as part of a combined management-based control program (Marco, personal communication).

There is active interest in the research and development of commercial vaccines against PCVD including PMWS. Preliminary evidence indicates that vaccines directed against PCV2 antigens are effective in reducing PCV2-associated pathology in challenge infections. This is despite the previously conflicting data on the association or not between PCV2 serological titre in piglets and subsequent predisposition to PMWS. For example one report identified piglets born to sows with high anti-PCV2 titres as being at greater risk of PMWS-associated mortality [71], while others proposed that high anti-PCV2 antibodies in piglets were protective against PMWS [72], and yet others found no association [73]. The group at Iowa State University developed a chimeric PCV incorporating the immunogenic capsid gene of PCV2 into a PCV1 backbone [74]. The chimeric virus, or its infectious DNA clone, led to an attenuated infection when administered by intramuscular injection and resulted in absence of viraemia and reduced lymphoid pathology following a subsequent PCV2 challenge. Work in France found good protection from PCV2-challenge induced pathology and reduced PCV2 viraemia following the administration of adjuvanted recombinant sub-unit proteins derived from ORF1 and ORF2 [75, 76]. Finally, Merial Animal Health SAS are currently in the process of clinical evaluation of an adjuvanted, inactivated PCV2 vaccine for use in breeding females in order to boost colostral immunity. Earlier studies had indicated a protective effect of inactivated PCV2 vaccines in a combined PCV2 and PRRSV challenge model [77].

In the absence of commercially available vaccination another immunological-based approach to control of active PMWS in the field has been to aim for a stabilised endemic herd-wide PMWS status as quickly as possible [65]. On individual farms this approach has employed techniques such as serum therapy, emphasis on good colostral intake, herd closure or extended quarantine for naïve incoming animals (to enable infection and stable immunity to develop), and sourcing of replacement gilts from a PMWS positive source.

As a final consideration for on-farm approaches to PMWS control, biosecurity remains a key issue. Standard biosecurity approaches do not appear to have prevented the entry of PMWS to herds that have been maintained free of enzootic pneumonia and PRRSV for over 10 years , or to countries with strict live animal import controls such as New Zealand. Confirming the former observation, Green’s UK epidemiological study highlighted proximity of <5 miles to an infected herd, and permitting visitors who may have been in contact with other pigs in the preceding 3 days as positive risk factors for infection [13]. These findings point to a potential role, worthy of further investigation, for both wildlife and humans in the transmission of PMWS.

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