CASE REPORT
Granuloma Annulare as an Isotopic Response to Herpes Zoster Jonathan Levy, Duane Barber, and Lynne Robertson
B a c k g ro u n d : W o lf's is o to p ic resp o n se is th e p h e n o m e n o n o f a n e w skin disease o c c u rrin g a t th e s ite o f a n o th e r u n re la te d and
a lre a d y he aled sk in d is o rd e r. M o s t cases in th e lite ra tu re re p o rt herpes zo s te r (HZ) as th e o rig in a l disease; h o w e ve r, th e is o to p ic resp on ses v a ry g re a tly . In c lu d in g th is case, o u r lite ra tu re search reve aled 32 cases o f is o to p ic g ra n u lo m a a n n u la re (GA) fo llo w in g HZ. C ase R e p o rt: A n 82 -yea r-old m a le p re se n te d w ith G A lo ca lize d to th e rig h t T9 d e rm a to m e th a t la te r appe ared a t o th e r s ite s on th e
tr u n k an d e x tre m itie s . The p a tie n t had an e p iso d e o f sh in g le s in v o lv in g th e sam e d e rm a to m e 4 years earlier. D is c u s s io n : To o u r k n o w le d g e , th is is th e fir s t case re p o rt o f G A o c c u rrin g in itia lly as an is o to p ic resp on se in an HZ scar and
s u b s e q u e n tly
b e c o m in g
g e n e ra liz e d . T h ir ty - e ig h t p e rc e n t (12 o f 32) o f p a tie n ts
w it h
is o to p ic
G A f o llo w in g
HZ w e re
im m u n o c o m p ro m is e d , w h ic h is s im ila r t o th e p u b lis h e d rate o f im m u n o d e fic ie n c y in p a tie n ts w ith HZ.
C o n te x te : La re a c tio n is o to p iq u e de W o lf c o n s is te en I'a p p a ritio n d un e n o u v e lle a ffe c tio n cu ta n e e au siege d un a u tre tro u b le
cuta ne, no n lie e t deja cica trise. Dans la p lu p a rt des cas d e c rits da ns la d o c u m e n ta tio n , la m a la d ie d 'o rig in e e st le zona, m ais les re a c tio n s is o to p iq u e s s o n t tre s va ria b le s. La rech erch e d o c u m e n ta ire a reve le I'e xiste n ce de 32 cas de g ra n u lo m e a n n u la ire (GA) is o to p iq u e , y c o m p ris ce lu i d e c rit ici, c o n s e c u tif au zona. E x p o s e d e c a s: Un h o m m e de 82 ans est ve n u c o n s u lte r p o u r un GA s itu e da ns le d e rm a to m e T9 d ro it, q u i est a p pa ru p lu s ta rd en
d 'a u tre s p o in ts su r le tro n c e t les m e m b re s. Le p a tie n t a v a it co n n u un e poussee de zona to u c h a n t le m e m e d e rm a to m e , q u a tre ans a u pa ravan t. D is c u s s io n s : II s 'a g it, a n o tre conna issan ce, du p re m ie r cas d e c rit de G A, q u i s 'e s t m a n ife s to d 'a b o rd c o m m e une re a ctio n
is o to p iq u e a un e c ic a tric e de zona e t q u i s 'e s t ge n e ra lise p a r la s u ite . Dans 38% (12 su r 32) des cas, le G A is o to p iq u e , c o n s e c u tif au zona e s t a p pa ru chez des p e rso n n e s a ya n t un sys te m e im m u n ita ire a ffa ib li; ce ta u x est c o m p a ra b le au ta u x p u b lie d 'im m u n o d e fic ie n c e chez les p a tie n ts a tte in ts de zona.
Case Report
An 82-year-old white male presented with a 1-year history of asymptomatic skin lesions on the trunk and extremities. These first appeared during a course of chemotherapy with
From the Division o f Dermatology and Cutaneous Sciences, Department o f Medicine, University o f Alberta, Edmonton, AB, and Calgary Laboratory Services and Department o f Pathology and Division o f Dermatology, Department o f Medicine, University o f Calgary, Calgary, AB. Presented at the 88th A nnual Canadian Dermatology Association Conference in Quebec City M ay 27, 2014, as a poster presentation. It was also awarded the “Best Poster Presentation by a Resident/Fellow at the Canadian Society for Investigative Dermatology” at the conference. Address reprint requests to: Jonathan Levy, BMSc, MD, Division of Dermatology and Cutaneous Sciences, 2-166 Clinical Sciences Building, 11350 - 83 Avenue, Edmonton, AB T6G 2G3.
DOI 10.2310/7750.2014.14019 © 2014 Canadian Dermatology Association
5-fluorouracil (5-FU) for cecal cancer. Skin lesions were initially localized to a dermatome on the right thorax and after several months began to appear at other body sites. The patient recalled having had an episode of shingles involving the same dermatome 4 years earlier. The herpes zoster (HZ) infection and postherpetic neuralgia had been treated with valacyclovir and gabapentin, respectively. The neuralgia had completely resolved 6 months later. The patient’s medical history was significant for T3N0M0 cecal cancer, which was managed by surgical resection and chemotherapy with capecitabine followed by the Roswell Park regimen (leucovorin and 5-FU). In addition, the patient had type 2 diabetes mellitus, hyperten sion, and gastroesophageal reflux disease. Medications at presentation included repaglinide, metformin, insulin, enalapril, hydrochlorothiazide, and pantoprazole. Examination revealed multiple erythematous, annular dermal papules and plaques on the right thorax within the right T9 dermatome (Figure 1). There were morphologically
DECKER^ \T7 Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 413-419
413
Levy et al
Figure 1. Granuloma annulare distributed in a zosteriform pattern along the right T9 dermatome.
similar lesions scattered on the extremities and trunk else where (Figure 2). Histologic evaluation of a plaque demonstrated inter stitial infiltrates of histiocytes and multinucleated giant cells separated by eosinophilic bundles of collagen consistent with the clinical diagnosis of granuloma annulare (GA) (Figure 3 and Figure 4). Several of the patient’s more conspicuous and pruritic lesions were effectively treated with intralesional triamci nolone acetonide (10 mg/mL). Additional therapies, including a 2-month trial of pentoxifylline 400 mg orally
Figure 2. Lesions of granuloma annulare are seen on the right arm, which is outside the original herpes zoster dermatome.
Figure 3. Low-power view showing a granulomatous inflammatory infiltrate composed of histiocytes and multinucleated giant cells infiltrating between bundles of collagen (hematoxylin and eosin stain; X40 original magnification).
three times daily and a 4-month trial of hydroxychlor oquine 200 mg twice daily, were ineffective. Medically supervised ultraviolet therapy was not a therapeutic option as he lived in a remote area. The patient elected not to pursue additional treatments.
Discussion In 1955, Wyburn-Mason reported 26 cases of nonmela noma skin cancer occurring at sites previously affected by HZ.1 Forty years later, Wolf and colleagues coined the term “isotopic response” to describe the phenomenon of a
Figure 4. Well-circumscribed collection of histiocytes and multi nucleated giant cells infiltrating between bundles of collagen (hematoxylin and eosin stain; X I00 original magnification).
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 413-419
Granuloma Annulare as an Isotopic Response to Herpes Zoster
new skin disease occurring at the same site of another unrelated and already healed skin disorder.2 This, they noted, was in contradistinction to the isomorphic response, which describes the occurrence of a preexisting skin disease at a site of injury. The term isotopic response is now well entrenched in the dermatology lexicon. Most of the cases in the literature report HZ as the original disease. The isotopic responses, however, vary greatly and include granulomatous reactions (GA, sarcoidosis), malignant tumors (basal cell carcinoma, squamous cell carcinoma, breast cancer, angio sarcoma, Kaposi sarcoma), dysimmune reactions (lichen planus, lichen sclerosus et atrophicus, graft-versus-host disease, linear IgA dermatosis), infections (viral, bacterial, fungal), and others (pseudolymphoma, mucinosis, xantho mas,3 psoriasis, morphea, acneiform eruption).4 GA is a common benign inflammatory disorder of unknown etiology. Implicated inciting mechanisms for the disease include insect bites, traum a, sun exposure, vaccination, and viral infection. GA was first reported as an isotopic response in 1978 by Guill and Goette. Since then, including our case, 32 cases of isotopic GA following HZ have been reported in the English literature (Table l).5-25 Most cases are of classic GA; however, other variants, such as perforating and subcutaneous GA, have also been reported. Published case reports show a slight predilection toward female patients (20 of 32 patients) with a mean age of 62.9 years. The majority of patients were treated with antivirals, and only 11 cases were complicated by postherpetic neuralgia. The median time to onset of GA following resolution of HZ virus was 2 to 3 months, and all cases but two were confined to the HZ scar sites. Contrary to this, our case appeared after a long latency of 3 years and appears to be the first report of generalization of the isotopic response outside of the previously affected dermatome(s). Twelve of the 32 patients (41%) reported in the literature were immunocompromised, presuming that when immune status is not reported, the patient is immunocompetent. Of these, seven had chronic lympho cytic leukemia and there was one case each of multiple myeloma, Hodgkin lym phoma, Lennert lymphoma, immunoblastic lymphoma, and cecal cancer. In a study of 5,274 patients with HZ, 31.4% were immunocompro mised due to an underlying condition.26 Given that this rate is similar to that seen in our population, an immunocompromised state may not necessarily predis pose to the development of an isotopic response following HZ infection. No discernible pattern to the location of the affected dermatome was noted, but interestingly, 65% (15 of 23) of
cases involved the right-sided dermatome (in cases where sidedness is reported). Also, 22% (7 of 32) of cases involved more than one dermatome, which is generally a rare finding. Treatm ent consisted of topical and/or intralesional corticosteroids, and GA lesions cleared on average in 1 to 2 months. The underlying mechanism of a HZ virus-related isotopic response is not known. A delayed hypersensitivity reaction to varicella-zoster virus (VZV) is one proposed mechanism. The fact that VZV DNA has not been detected by polymerase chain reaction from granulomatous lesions older than 1 m onth1'1,27,28 implies that it is not directly implicated in the pathogenesis of the isotopic granuloma tous reactions. The occurrence of GA may instead represent a delayed hypersensitivity reaction to VZV glycoproteins or altered tissue antigens.2,16,17,29,30 Postinflammatory altera tions in the microvasculature may be a contributing factor to the localization of a different second disease.31 Another proposed mechanism involves local immune dysregulation resulting from VZV-induced sensory nerve damage and a change in the balance of neuropeptides released from cutaneous nerve endings. This hypothesis may explain the diversity of diseases that subsequently localize within that cutaneous region.4 Regardless of the pathophysiologic mechanism, the term immunocompromised district has been proposed to explain the vulnerability of a cutaneous region that has undergone herpetic infections to the development of immune disorders, infections, and tumors.4 An im muno compromised district may also provide the stage for the occurrence of the Koebner and inverse Koebner (Renbok) phenomena. The Renbok phenomenon, first described in 1991, refers to the conspicuous absence of a skin disease in an area affected by trauma.32 Since then, the Renbok phenomenon has almost exclusively been described in cases of alopecia areata with sparing of alopecia occurring in psoriasis plaques,33-38 congenital nevi,39 and nevus flammeus.40 The only case of the Renbok phenomenon not involving alopecia areata was described by Kroth and colleagues, in which disseminated cutaneous graft-versushost disease spared the dermatome previously affected by HZ.41 Its pathophysiology may be attributed to the competition between two separate immunologic processes that either promote or suppress one disease. We report a case of GA occurring as an isotopic response in an area previously affected by HZ. The unique features of this case are the long latency between the HZ virus episode and onset of the isotopic response and the generalization of the response outside the pre viously affected dermatome. Future studies examining
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 413-419
415
Levy et al
60
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Granuloma Annulare as an Isotopic Response to Herpes Zoster Jonathan Levy, Duane Barber, and Lynne Robertson
B a c k g ro u n d : W o lf's is o to p ic resp o n se is th e p h e n o m e n o n o f a n e w skin disease o c c u rrin g a t th e s ite o f a n o th e r u n re la te d and
a lre a d y he aled sk in d is o rd e r. M o s t cases in th e lite ra tu re re p o rt herpes zo s te r (HZ) as th e o rig in a l disease; h o w e ve r, th e is o to p ic resp on ses v a ry g re a tly . In c lu d in g th is case, o u r lite ra tu re search reve aled 32 cases o f is o to p ic g ra n u lo m a a n n u la re (GA) fo llo w in g HZ. C ase R e p o rt: A n 82 -yea r-old m a le p re se n te d w ith G A lo ca lize d to th e rig h t T9 d e rm a to m e th a t la te r appe ared a t o th e r s ite s on th e
tr u n k an d e x tre m itie s . The p a tie n t had an e p iso d e o f sh in g le s in v o lv in g th e sam e d e rm a to m e 4 years earlier. D is c u s s io n : To o u r k n o w le d g e , th is is th e fir s t case re p o rt o f G A o c c u rrin g in itia lly as an is o to p ic resp on se in an HZ scar and
s u b s e q u e n tly
b e c o m in g
g e n e ra liz e d . T h ir ty - e ig h t p e rc e n t (12 o f 32) o f p a tie n ts
w it h
is o to p ic
G A f o llo w in g
HZ w e re
im m u n o c o m p ro m is e d , w h ic h is s im ila r t o th e p u b lis h e d rate o f im m u n o d e fic ie n c y in p a tie n ts w ith HZ.
C o n te x te : La re a c tio n is o to p iq u e de W o lf c o n s is te en I'a p p a ritio n d un e n o u v e lle a ffe c tio n cu ta n e e au siege d un a u tre tro u b le
cuta ne, no n lie e t deja cica trise. Dans la p lu p a rt des cas d e c rits da ns la d o c u m e n ta tio n , la m a la d ie d 'o rig in e e st le zona, m ais les re a c tio n s is o to p iq u e s s o n t tre s va ria b le s. La rech erch e d o c u m e n ta ire a reve le I'e xiste n ce de 32 cas de g ra n u lo m e a n n u la ire (GA) is o to p iq u e , y c o m p ris ce lu i d e c rit ici, c o n s e c u tif au zona. E x p o s e d e c a s: Un h o m m e de 82 ans est ve n u c o n s u lte r p o u r un GA s itu e da ns le d e rm a to m e T9 d ro it, q u i est a p pa ru p lu s ta rd en
d 'a u tre s p o in ts su r le tro n c e t les m e m b re s. Le p a tie n t a v a it co n n u un e poussee de zona to u c h a n t le m e m e d e rm a to m e , q u a tre ans a u pa ravan t. D is c u s s io n s : II s 'a g it, a n o tre conna issan ce, du p re m ie r cas d e c rit de G A, q u i s 'e s t m a n ife s to d 'a b o rd c o m m e une re a ctio n
is o to p iq u e a un e c ic a tric e de zona e t q u i s 'e s t ge n e ra lise p a r la s u ite . Dans 38% (12 su r 32) des cas, le G A is o to p iq u e , c o n s e c u tif au zona e s t a p pa ru chez des p e rso n n e s a ya n t un sys te m e im m u n ita ire a ffa ib li; ce ta u x est c o m p a ra b le au ta u x p u b lie d 'im m u n o d e fic ie n c e chez les p a tie n ts a tte in ts de zona.
Case Report
An 82-year-old white male presented with a 1-year history of asymptomatic skin lesions on the trunk and extremities. These first appeared during a course of chemotherapy with
From the Division o f Dermatology and Cutaneous Sciences, Department o f Medicine, University o f Alberta, Edmonton, AB, and Calgary Laboratory Services and Department o f Pathology and Division o f Dermatology, Department o f Medicine, University o f Calgary, Calgary, AB. Presented at the 88th A nnual Canadian Dermatology Association Conference in Quebec City M ay 27, 2014, as a poster presentation. It was also awarded the “Best Poster Presentation by a Resident/Fellow at the Canadian Society for Investigative Dermatology” at the conference. Address reprint requests to: Jonathan Levy, BMSc, MD, Division of Dermatology and Cutaneous Sciences, 2-166 Clinical Sciences Building, 11350 - 83 Avenue, Edmonton, AB T6G 2G3.
DOI 10.2310/7750.2014.14019 © 2014 Canadian Dermatology Association
5-fluorouracil (5-FU) for cecal cancer. Skin lesions were initially localized to a dermatome on the right thorax and after several months began to appear at other body sites. The patient recalled having had an episode of shingles involving the same dermatome 4 years earlier. The herpes zoster (HZ) infection and postherpetic neuralgia had been treated with valacyclovir and gabapentin, respectively. The neuralgia had completely resolved 6 months later. The patient’s medical history was significant for T3N0M0 cecal cancer, which was managed by surgical resection and chemotherapy with capecitabine followed by the Roswell Park regimen (leucovorin and 5-FU). In addition, the patient had type 2 diabetes mellitus, hyperten sion, and gastroesophageal reflux disease. Medications at presentation included repaglinide, metformin, insulin, enalapril, hydrochlorothiazide, and pantoprazole. Examination revealed multiple erythematous, annular dermal papules and plaques on the right thorax within the right T9 dermatome (Figure 1). There were morphologically
DECKER^ \T7 Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 413-419
413
Levy et al
Figure 1. Granuloma annulare distributed in a zosteriform pattern along the right T9 dermatome.
similar lesions scattered on the extremities and trunk else where (Figure 2). Histologic evaluation of a plaque demonstrated inter stitial infiltrates of histiocytes and multinucleated giant cells separated by eosinophilic bundles of collagen consistent with the clinical diagnosis of granuloma annulare (GA) (Figure 3 and Figure 4). Several of the patient’s more conspicuous and pruritic lesions were effectively treated with intralesional triamci nolone acetonide (10 mg/mL). Additional therapies, including a 2-month trial of pentoxifylline 400 mg orally
Figure 2. Lesions of granuloma annulare are seen on the right arm, which is outside the original herpes zoster dermatome.
Figure 3. Low-power view showing a granulomatous inflammatory infiltrate composed of histiocytes and multinucleated giant cells infiltrating between bundles of collagen (hematoxylin and eosin stain; X40 original magnification).
three times daily and a 4-month trial of hydroxychlor oquine 200 mg twice daily, were ineffective. Medically supervised ultraviolet therapy was not a therapeutic option as he lived in a remote area. The patient elected not to pursue additional treatments.
Discussion In 1955, Wyburn-Mason reported 26 cases of nonmela noma skin cancer occurring at sites previously affected by HZ.1 Forty years later, Wolf and colleagues coined the term “isotopic response” to describe the phenomenon of a
Figure 4. Well-circumscribed collection of histiocytes and multi nucleated giant cells infiltrating between bundles of collagen (hematoxylin and eosin stain; X I00 original magnification).
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 413-419
Granuloma Annulare as an Isotopic Response to Herpes Zoster
new skin disease occurring at the same site of another unrelated and already healed skin disorder.2 This, they noted, was in contradistinction to the isomorphic response, which describes the occurrence of a preexisting skin disease at a site of injury. The term isotopic response is now well entrenched in the dermatology lexicon. Most of the cases in the literature report HZ as the original disease. The isotopic responses, however, vary greatly and include granulomatous reactions (GA, sarcoidosis), malignant tumors (basal cell carcinoma, squamous cell carcinoma, breast cancer, angio sarcoma, Kaposi sarcoma), dysimmune reactions (lichen planus, lichen sclerosus et atrophicus, graft-versus-host disease, linear IgA dermatosis), infections (viral, bacterial, fungal), and others (pseudolymphoma, mucinosis, xantho mas,3 psoriasis, morphea, acneiform eruption).4 GA is a common benign inflammatory disorder of unknown etiology. Implicated inciting mechanisms for the disease include insect bites, traum a, sun exposure, vaccination, and viral infection. GA was first reported as an isotopic response in 1978 by Guill and Goette. Since then, including our case, 32 cases of isotopic GA following HZ have been reported in the English literature (Table l).5-25 Most cases are of classic GA; however, other variants, such as perforating and subcutaneous GA, have also been reported. Published case reports show a slight predilection toward female patients (20 of 32 patients) with a mean age of 62.9 years. The majority of patients were treated with antivirals, and only 11 cases were complicated by postherpetic neuralgia. The median time to onset of GA following resolution of HZ virus was 2 to 3 months, and all cases but two were confined to the HZ scar sites. Contrary to this, our case appeared after a long latency of 3 years and appears to be the first report of generalization of the isotopic response outside of the previously affected dermatome(s). Twelve of the 32 patients (41%) reported in the literature were immunocompromised, presuming that when immune status is not reported, the patient is immunocompetent. Of these, seven had chronic lympho cytic leukemia and there was one case each of multiple myeloma, Hodgkin lym phoma, Lennert lymphoma, immunoblastic lymphoma, and cecal cancer. In a study of 5,274 patients with HZ, 31.4% were immunocompro mised due to an underlying condition.26 Given that this rate is similar to that seen in our population, an immunocompromised state may not necessarily predis pose to the development of an isotopic response following HZ infection. No discernible pattern to the location of the affected dermatome was noted, but interestingly, 65% (15 of 23) of
cases involved the right-sided dermatome (in cases where sidedness is reported). Also, 22% (7 of 32) of cases involved more than one dermatome, which is generally a rare finding. Treatm ent consisted of topical and/or intralesional corticosteroids, and GA lesions cleared on average in 1 to 2 months. The underlying mechanism of a HZ virus-related isotopic response is not known. A delayed hypersensitivity reaction to varicella-zoster virus (VZV) is one proposed mechanism. The fact that VZV DNA has not been detected by polymerase chain reaction from granulomatous lesions older than 1 m onth1'1,27,28 implies that it is not directly implicated in the pathogenesis of the isotopic granuloma tous reactions. The occurrence of GA may instead represent a delayed hypersensitivity reaction to VZV glycoproteins or altered tissue antigens.2,16,17,29,30 Postinflammatory altera tions in the microvasculature may be a contributing factor to the localization of a different second disease.31 Another proposed mechanism involves local immune dysregulation resulting from VZV-induced sensory nerve damage and a change in the balance of neuropeptides released from cutaneous nerve endings. This hypothesis may explain the diversity of diseases that subsequently localize within that cutaneous region.4 Regardless of the pathophysiologic mechanism, the term immunocompromised district has been proposed to explain the vulnerability of a cutaneous region that has undergone herpetic infections to the development of immune disorders, infections, and tumors.4 An im muno compromised district may also provide the stage for the occurrence of the Koebner and inverse Koebner (Renbok) phenomena. The Renbok phenomenon, first described in 1991, refers to the conspicuous absence of a skin disease in an area affected by trauma.32 Since then, the Renbok phenomenon has almost exclusively been described in cases of alopecia areata with sparing of alopecia occurring in psoriasis plaques,33-38 congenital nevi,39 and nevus flammeus.40 The only case of the Renbok phenomenon not involving alopecia areata was described by Kroth and colleagues, in which disseminated cutaneous graft-versushost disease spared the dermatome previously affected by HZ.41 Its pathophysiology may be attributed to the competition between two separate immunologic processes that either promote or suppress one disease. We report a case of GA occurring as an isotopic response in an area previously affected by HZ. The unique features of this case are the long latency between the HZ virus episode and onset of the isotopic response and the generalization of the response outside the pre viously affected dermatome. Future studies examining
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 413-419
415
Levy et al
60
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