 |
 |
|
|
|
Recent studies report that seasonal and, in general, environmental changes significantly influence the onset and course of panic disorder (PD), especially in comparison with other anxiety disorders (1). In fact, although PD is defined as a chronic disorder, long periods of remission alternating with periods of exacerbated symptomatology are observed, particularly in summer (1–4). Various studies report more frequent onset of the disorder between March and August (2,5,6). Moreover, most patients (76%) experience their first panic attack (PA) during the day (between 6:00 AM and 6.00 PM) (7,8). Morning attacks are more common than evening ones (6). However, recrudescence in winter (that is, during December and January) with well-being during the rest of the year is sometimes described; in these cases, PD is often comorbid with a seasonal affective disorder (SAD) or a subsyndromic SAD, and a recurrence of panic attacks coincides with mood changes (9,10). Therefore, PD with winter relapses may represent a variant of SAD (11). We could also assume the existence of 2 kinds of PD (one with summer worsening and the other with winter aggravation of the symptomatology), each demonstrating a different etiopathogenesis and clinical course (2). Of the several environmental variables with a seasonal pattern, light stimulation seems to be most implicated in the complex pathogenic mechanism of PD. This is confirmed both by recent research data and by clinical evidence. For example, intermittent fluorescent light can bring about a violent anxious reaction (in particular, somatic symptoms typical of PA and depersonalization–derealization symptoms, rather than cognitive and behavioural elements) in patients with PD or agoraphobia (12,13). Clinically phobic behaviour is often described in patients with PD. Instinctively, they take shelter from light by wearing dark glasses; they prefer winter to summer; they choose shady places; and they avoid sun exposure at midday and vacations at the sea in summer (7,14). The sensitivity to light exhibited by patients with PD raises a question about the structures involved in these phenomena. McIntyre hypothesizes a pineal gland dysfunction that leads to excessive sensitivity to environmental light variations (15). This dysfunction may arise when the first 3 months of postnatal life coincide with a poor light stimulation period (16,17). Some authors suggest that the retinal structures are involved in the PD pathogenesis—an involvement related to the development of the central nervous system (CNS), particularly the primary visual cortex, which is specifically influenced by environmental light stimuli (18,19). In a retrospective study carried out in our institute, a peculiar seasonal distribution of birth dates in patients affected by PD was observed; specifically, birth dates in autumn and winter increased, with a peak in September (1). Therefore, we hypothesize that lack of light exposure in the early months following birth, which is fundamental for the development of the CNS and visual structures, may be a predisposing factor for PD onset. Dopamine is the most studied retinal neurotransmitter; it seems to play a major role in the transmission of light stimuli (20–22). Moreover, all disorders linked to a dopaminergic system disturbance, specifically, substance-induced psychotic disorders (23), psychomotor excitement of bipolar disorder (2,24–29), and some features of the schizophrenia spectrum (25,30–34) worsen in summer. Light may induce panic attacks through a dopaminergic pathway; in fact, dopamine agonist substances (for example, cocaine and levodopa) can bring about panic attacks (35–36). The serotonergic system has also been brought up in the attempt to explain light hypersensitivity in patients with PD. This system undergoes significant changes during the year in relation to climatic and environmental parameters, especially the photoperiod. Klein presumes an influence of the serotonergic system in PD pathogenesis through a modulation of other, mainly norepinephrine, neurotransmitters (37,38). Aside from biological structures involved in the relation between light and PD, light hypersensitivity, which underlies photophobic behaviour, does not seem to be a specific trait of PD (3,39). However, it is widely found in other psychiatric disorders, such as certain mood disorders (for example, SAD; 40) and psychotic disorders (3). Therefore, photosensitivity may be depicted as a transnosographic dimension expressed in different ways in various psychiatric disorders (2). The relatively frequent finding of photophobia in patients with PD, as shown by clinical observation and data in the literature, leads us to the conjecture that photosensitivity is a relatively stable dimension of the panic-agoraphobic spectrum that includes agoraphobia, hypochondriasis, and substance and medication sensitivity (41). Recently, the application of the spectrum model to PD and other psychiatric disorders has become more widespread. This model proposes to fill the gap between the categories that meet DSM criteria and prodromal, residual, subclinical, and atypical states of psychiatric disorders. The wide range of symptoms included in the spectrum can be associated with high levels of discomfort and maladjustment, even when the evident disorder is absent, and in the presence of an Axis I disorder, can interfere with the choice and efficacy of treatment. The need for adequate assessment instruments applicable to a spectrum model has led to the elaboration of specific structured clinical interviews, such as the Structured Clinical Interview for Panic-Agoraphobic Spectrum (SCI-PAS), designed to assess panic-agoraphobic spectrum. This instrument is available in a lifetime version (SCI-PAS-Lifetime), a last-month version (SCI-PAS-Last Month) and a last-week version (SCI-PAS-Last Week) (40). Perugi and others outline a set of preexisting and egosyntonic subthreshold symptoms that indicate a temperament predictive of PD; it is represented by increased activity of the sympathetic system, with sporadic and isolated symptoms such as dyspnoea, palpitations, sweating, heat intolerance, dizziness, and feelings of instability. Also belonging to the panic-agoraphobic spectrum are hypochondriasis; sensitivity to loss; difficulty in leaving one’s home environment, with consequent reduced explorative behaviour; high need for reassurance; and sensitivity to substances and medications, especially caffeine and stimulants such as cocaine and amphetamine (42). The continuity between the evident disorder and spectrum symptoms suggests that the the same pathogenetic factors exist; for both conditions, light hypersensitivity may be one of these factors. Although the spectrum model is applied more and more frequently, there have been no studies of light sensitivity and season of birth in subjects exhibiting panic-agoraphobic spectrum features, although they do exist in the sphere of diagnosed PD. Investigating light sensitivity in these subjects may help to clarify the relation between photosensitivity and PD and its spectrum; it may also help the assessment of whether this dimension represents a state component exclusively present in patients with PD at appraisal time only or a trait component that is detectable in the absence of PD criteria but associated, in any case, with panic-agoraphobic spectrum elements. Our study, therefore, aimed to verify whether there is a correlation between the panic-agoraphobic spectrum and photosensitivity. We investigated photosensitivity in its subdimensional entities, photophobia and photophilia. Another study aim was to provide an outside test of validity and reliability for the panic-agoraphobic spectrum model, which is presently supported by clinical evidence only. If both the panic-agoraphobic spectrum and PD showed similar epidemiological and clinical data—for example, a similar relation to photosensitivity measures—that finding would further support the spectrum model, because the latter would prove more closely correlated to PD. MethodsWe recruited the study sample at random from the general population resident in the municipality of Siena. Of 169 subjects, 109 were women (64.5%), and 60 were men (35.5%). They ranged between age 19 and age 66 years (mean 26.53 years, SD 9.49), and we selected them to be homogeneously distributed by month of birth. Participants were recruited by telephone and interviewed at the Department of Neuroscience, Division of Psychiatry, University of Siena. The study, performed according to the dictates of the Helsinki Declaration (43), was approved by the university’s ethical committee. All participants provided informed consent. Only healthy and drug-free subjects were included in the study. We administered the Mini International Neuropsychiatric Interview (MINI, 44) to exclude subjects with psychiatric disorders. From their case histories, we identified and excluded subjects affected by general medical conditions. Each subject completed the SCI-PAS-Lifetime and the Photosensitivity Assessment Questionnaire (PAQ). We used the SCI-PAS-Lifetime to assess the panic-agoraphobic spectrum (39). It comprises 114 items grouped according to the following 8 domains: 1) separation sensitivity (divided into 2 sections, separation anxiety and loss sensitivity), 2) panic-like symptoms (including one section for typical panic-like symptoms and another section for atypical panic-like symptoms), 3) stress sensitivity, 4) substance and medication sensitivity (consisting of 2 sections, substance sensitivity and medication phobia), 5) anxious expectation (that is, anticipatory anxiety and alarm state), 6) agoraphobia (with typical and atypical symptoms), 7) illness-related phobia, 8) reassurance orientation (divided into help-seeking, counterphobic measures, and dramatization). We established that each domain was fulfilled if the interviewed subject affirmatively answered more than 3 questions for domains 1, 2, 4, 5, 6, 7, and 8, as well as 2 questions for field 3. It is also possible to consider the total score formed by the sum of items with an affirmative answer. The PAQ, used to investigate light sensitivity (Table 1), tests photophobic and photophilic behaviour. It has recently been validated in the Italian population (45). The PAQ has 16 items, 8 of which are related to avoidance behaviours (the photophobia subdimension) and 8 of which are related to light-seeking behaviour (the photophilia subdimension). The total score of each subdimension is formed by the sum of its items having an affirmative answer (46,47).
We used the SPSS statistical package for scientific research (48) to process data, employing either the Spearman rank correlation coefficient for bivariate data or the Mann–Whitney U test. We chose these applications because some variables were not normally distributed. We set a significance level of P < 0.05. ResultsWe found a Gaussian distribution for SCI-PAS-Lifetime scores; the mean SCI-PAS-Lifetime total score was 27.37, SD 15.5. The scores on the PAQ were as follows: for photophobia, mean 2.57, SD 2.29; for photophilia, mean 5.4, SD 2.37. Photophobia scores did not show a Gaussian distribution: the frequency of low scores was greater, in the range of the general Italian population, and scores appeared significantly lower than those obtained from PD patients in an earlier study (46) (mean 2.57, SD 2.29 and mean 6.22, SD 1.98, respectively; P < 0.001). Photophilia scores also did not show a Gaussian distribution, yielding a greater frequency of high scores. Comparing the results obtained from the 2 questionnaires, we found that the SCI-PAS-Lifetime total score was positively correlated with the total score of the PAQ photophobia subdimension (r = 0.44; P < 0.001). Conversely, the SCI-PAS-Lifetime total score was not significantly correlated with the photophilia subdimension (r = 0.06; P = 0.47) (Figure 1). Figure 1 Scattergram of the correlations between SCI-PAS-Lifetime total score (SCI-PAS total score) and photophobia (Pho total score) and photophillia (Phi total score) PAQ subdimensions.  In our sample, the SCI-PAS-Lifetime scores of almost all single domains were significantly correlated among themselves and followed a direct linear relation. This positive correlation was also evident between the PAQ photophobia subdimension and SCI-PAS-Lifetime single domains. In fact, we observed that, as photophobia increased, scores on all SCI-PAS-Lifetime domains increased significantly (Table 2). Bivariate correlation showed higher coefficient correlation between the panic-like symptoms domain and photophobia (r = 0.44; P < 0.001).
Positivity for each SCI-PAS-Lifetime domain was determined by the threshold we established. When we employed the Mann–Whitney U test, the photophobia level was significantly higher in subjects who showed positivity in the following domains: separation sensitivity (P < 0.001), panic-like symptoms (P = 0.001), substance and medication sensitivity (P = 0.003), agoraphobia (P < 0.001), and reassurance orientation (P < 0.001) (Table 3). Conversely, we found a significantly higher photophilia level only among subjects with positivity in the anxious expectation domain (P = 0.03).
DiscussionA high total score in the SCI-PAS, which indicates more typical features of the spectrum, is associated with a higher level of light sensitivity and intolerance of bright stimuli. This finding reflects clinical evidence that widely documents photophobic behaviours in subjects with PD as well as the importance of light stimuli exposure during the onset and course of such a disorder (2–4,6–8). Thus bright stimulation seems to be relevant both for subjects with PD diagnosed according to current DSM criteria and for those suffering from the panic-agoraphobic spectrum, with symptoms ranging from obvious disorder through subclinical states to a condition approaching normal. We have not considered the relation between the panic-agoraphobic spectrum and the general aversion to stimuli (that is, not only bright but also sensory and somatic stimuli) that characterizes PD (49). This stimuli aversion is partially considered in the SCI-PAS- Lifetime section related to atypical panic-like symptoms. Indeed, even separate panic spectrum dimensions—separation sensitivity, panic-like symptoms, stress sensitivity, substance and medication sensitivity, anxious expectation, agoraphobia, illness-related phobia, and reassurance orientation—are proportionally increased with increased photophobia. Interestingly, panic-like symptoms is the dimension most correlated with photophobia. Panic attack symptoms are the prevalent element in DSM-IV diagnostic criteria for PD, and following a model that postulates the existence of a continuum between PD and the panic-agoraphobic spectrum, we can suppose that subjects with a considerable number of panic symptoms are near the PD clinical threshold. According to this hypothesis, high photophobia levels will be found more frequently in patients affected by PD and in subjects who are close to meeting its diagnostic criteria. Whether light sensitivity is a pathogenic element of PD and its associated manifestations, and therefore a prior and predisposing factor in the development of such syndromes, or whether it is, rather, a consequence of the onset of a panic-agoraphobic spectrum condition remains an open question. Photosensitivity itself may thus represent a dimensional entity of this spectrum. PD, its spectrum, and photophobia may also be epiphenomena of the same biological, neurostructural, or neurochemical changes probably implied in PD pathogenesis. By contrast, photophilia seems to be an independent subdimension when it is compared with characteristic panic spectrum elements, a finding confirming the results of a recent study that demonstrated higher photophobic scores, but not lower photophilic ones, in patients affected by PD, compared with control subjects (46). Conversely, we cannot explain the presence of higher levels of photophobia in subjects scoring positive in the anxious expectation domain of the SCI-PAS-Lifetime, nor are there any data about this topic in the literature. This finding suggests to us that anxious expectation is a dimension more tightly correlated to mood disorders such as generalized anxiety disorder (50), which can be associated with photophobic behaviours. A significant relation between light sensitivity and the panic-agoraphobic spectrum has interesting etiopathogenetic and clinical implications. Light hypersensitivity has often been considered a possible factor of panic attack pathogenesis, and several studies suggest a neurobiological hypothesis to explain the relation between light and panic attacks (15–20). Our data also seem to confirm the existence of such a relation in the panic spectrum, suggesting the importance of further studies to more carefully investigate etiopathogenetic factors and their relation to panic-agoraphobic dimensions. The possible presence of panic spectrum elements in patients affected by psychiatric disorders other than PD, and their relation to light hypersensitivity, suggests the importance of carefully assessing subsyndromal panic symptoms. These subsyndromal symptoms may explain seasonal changes in some aspects of the course of clinical Axis I disorders (for example, depressive episodes with summer recurrences), even though patients may not be directly sensitive to environmental light changes. Therapeutic implications may also be significant. Finally, the correlation between light sensitivity and spectrum phenomena, as well as the correlation between light sensitivity and clinically evident PD, provides an outside assessment of the panic-agoraphobic spectrum and attests to its uniformity and internal consistency. It contributes to justifying the extensive development and diffusion of such a model to overcome the limitations of current psychiatric nosography. Our study presents some limitations. We studied a small sample that was not homogeneously distributed between men and women. Moreover, photophobia and photophilia scores did not show a Gaussian distribution. Further, the PAQ was designed for a Mediterranean population, and its outside test validity and reliability were evaluated in an Italian population only. Further studies are therefore needed to conduct a more in-depth investigation of the relations among the spectrum model, nosographic entities of current classification systems, and light sensitivity, using larger samples with a broad age range and a homogeneous sex distribution. Finally, we did not consider evaluating biological variables potentially involved in light stimulation reactions and the influence of therapy on the relations between environmental factors (particularly light) and the clinical and biological elements of different psychiatric disorders. This appears to be necessary for the further development of knowledge related to the topics investigated. References1. Castrogiovanni P, Iapichino S, Pacchierotti C, Pieraccini F. Season of birth in panic disorder. Neuropsychobiol 1999;40:177–82. 2. Castrogiovanni P, Pieraccini F, Iapichino S, Pacchierotti C. Stagionalità e esordio-decorso dei disturbi psichiatrici. In: Castrogiovanni P, Pieraccini F, Iapichino S, Pacchierotti C, editors. Stagionalità in psichiatria. Firenze: Società Editrice Europea; 1999. p 41–121. 3. Gerbaldo H, Cassady S, Maurer K, Pieschl D. The assessment of light intensity preference in psychiatric patients: a questionnaire. Acta Psychiatr Scand 1997;95:236–41. 4. Lelliot P, Marks I, McNamee G, Tobena A. Onset of panic disorder with agoraphobia. Arch Gen Psychiatry 1989;46:1000–4. 5. Castrogiovanni P, Pieraccini F, Iapichino S, Pacchierotti C. Distribuzione delle nascite nella popolazione generale. In: Castrogiovanni P, Pieraccini F, Iapichino S, Pacchierotti C, editors. Stagionalità in psichiatria. Firenze: Società Editrice Europea; 1999. p 123–51. 6. Kenardy J, Fried L, Kraemer HG, Taylor CB. Psychological precursors of panic attacks. Br J Psychiatry 1992;160:668–75. 7. Hoehn-Saric R. Benzodiazepine sensitivity in panic disordeer. Arch Gen Psychiatry 1991;48:669–71. 8. Lepine JP, Chignon JM, Teherani M. Suicidal behavior and onset of panic disorder. Arch Gen Psychiatry 1991;48:668–9. 9. Cameron OG. Frequency of panic disorder in summer. Am J Psychiatry 1989;146:123. 10. Marriott PF, Greenwood KM, Armstrong SM. Seasonality in panic disorder. J Affect Disord 1994;31:75–80. 11. Sandyk R, Dann LC. Seasonal panic disorder: a possible variant of seasonal affective disorder. Int J Neurosci 1992;62:263–7. 12. Eysel UT, Burandt U. Fluorescent light evokes flicker responses in visual neurons. Vision Res 1984;24:943–4. 13. Hazel J, Wilkins AJ. A contribution of fluorescent lighting to agoraphobia. Psychol Med 1990;20:591–6. 14. Keller MB, Baker LA. The clinical course of panic disorder and depression. J Clin Psychiatry 1992;53(Suppl 3):5–8. 15. Mc Intyre IM. Plasma concentrations of melatonin in panic disorder. Am J Psychiatry 1990;147:462–4. 16. Rafaelsen O, Gjierris A. Peptide levels in depression. Psychiatric Topics 1985;3:1. 17. Souètre E. Circadian rhythms in depression and recovery: evidence for blunted amplitude as main chronobiological abnormality. Psychiatr Res 1989;28:263–78. 18. Castrogiovanni P, Pieraccini F, Iapichino S, Pacchierotti C, Bossini L, Truglia E, and others. Electroretinogram B-Wave amplitude in panic disorder. CNS Spectrum 2001;3:210–3. 19. Kandel ER. Esperienza precoce, periodi critici e regolazione fine dello sviluppo dell’architettura cerebrale. In: Kandel ER, Schwartz JH, editors. Principi di neuroscienze. Milano: Ambrosiana; 1988. p 799–813. 20. Carlsson A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol Rev 1959;11:490–3. 21. Haggendal J, Malforms T. Identification and localization of the catecholamines in the retina and the choroid of the rabbit. Acta Phisiol Scand 1965;64:58–66. 22. Witkovsky P, Elred W. Catecholamine and indolamine-containing neurons in the turtle retina. J Comp Neurol 1984;228:217–25. 23. Poikolainen K. Seasonality of alcohol-related hospital admissions has implications for prevention. Drug Alcohol Depend 1982;10:65–9. 24. Frangos E. Seasonality of the episodes of recurrent affective psychoses. Possible prophylactic interventions. J Affect Disord 1982;2:239-47. 25. Hare EH, Walter SD. Seasonal variation in admission of psychiatric patients and its relation to seasonal variation in their births. J Epidemiol Comm Health 1978;32:47–52. 26. Martino V. Andamento circa annuale dei ricoveri per mania. Riv Sper Feniatria 1985;4:109. 27. Myers DH, Davies P. The seasonal incidence of mania and its relationship to climatic variables. Psychol Med:1978;8:433–40. 28. Parker G, Walter S. Seasonal variation in depressive disorders and suicidal deaths in New South Wales. Br J Psychiatry 1982;140:626–32. 29. Symonds RI, Williams P. Seasonal variation in the incidence of mania. Br J Psychiatry 1976;129:45–8. 30. Abe K. Seasonal fluctuation of psychiatric admissions, based on the data for seven prefecture of Japan for seven-year period 1955–1961, with a review of literature. Folia Psychiatr Neurol Jpn 1963;17:101. 31. Evenson RC, Altan H. Disturbing behavior: a study of incident reports. Psychiatr Q 1974;48:266–75. 32. McDonald JM. Homicidal threats. Am J Psychiatry 1967;124:475–82. 33. Shader RI, Jackson AH. Patterns of violent behavior among schizophrenic inpatients. Dis Nerv Syst 1977;38:13–6. 34. Zitrin A, Hardesty AS. Crime and violence among mental patients. Am J Psychiatry 1976;133:142–9. 35. Hebert MA, Blanchard DC, Blanchard RJ. Intravenous cocaine precipitates panic-like flight responses and lasting hyperdefensiveness in laboratory rats. Pharmacol Biochem Behav 1999;63:349–60. 36. Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P, Garcia-Urra D. “Panic attacks” in Parkinson’s disease. A long-term complication of levodopa therapy. Acta Neurol Scand 1993;87:14–8. 37. Cagampang FR, Inouye ST. Diurnal and circadian changes of serotonin in the suprachiasmatic nuclei: regulation by light and an endogenous pacemaker. Brain Res 1994;639:175–9. 38. Marazziti D, Falcone MF, Castrogiovanni P, Cassano GB. Seasonal serotonin uptake changes in healthy subjects. Mol Chem Neuropathol 1990;13:145–54. 39. Kellner M, Wiedemann K, Zihl J. Illumination perception in photophobic patients suffering from panic disorder with agoraphobia. Acta Psychiatr Scand 1997;96:72–4. 40. Rucci P, Maser JD. Instrument development in Italy–USA Collaborative Spectrum Project. Epidemiol Psichiatr Soc 2000;9:249–56. 41. Cassano GB, Michelini S, Shaer KM, Coli E, Maser JD, Franck E. The panic-agoraphobic spectrum: a descriptive approach to the assessment and treatment of subtle symptoms. Am J Psychiatry 1997;54:27–38. 42. Perugi G, Toni C, Benedetti A, Simonetti B, Simoncini M, Torti C, and others. Delineating a putative phobic-anxious temperament in 126 panic-agoraphobic patients: toward a rapprochement of European and US views. J Affect Disord 1998;47:11–23. 43. World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. Available: http://www.wma.net/e/policy/b3.htm. Accessed 2004 Sept 29. 44. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, and others. The Mini International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(Suppl 20):22–33. 45. De Capua A, Pacchierotti C, Iapichino S, Bossini L, Pieraccini F, Castrogiovanni P. Elaborazione e validazione di un Questionario di Valutazione della Fotosensibilità (QVF). Bollettino di Psicologia Applicata. Forthcoming. 46. Morana F, Iapichino S, Pacchierotti C, Bossini L, Castrogiovanni P. Sensibilità alla luce: confronto fra disturbo bipolare e disturbo di panico. Giornale Italiano di Psicopatologia 2001;7:372–7. 47. Morana F, Iapichino S, Pacchierotti C, Bossini L, Castrogiovanni P. Questionario per la valutazione della fotosensibilità: applicazioni nella popolazione italiana. Studi di Psichiatria 2002;4:21–5. 48. SPSS Inc. Statistical Package for Social Sciences. Version 11.5 for Windows. Chicago (IL): SPSS Inc; 2002. 49. Perugi G, Toni C, Musetti L, Petracca A, Cassano GB. Disturbo di panico e agorafobia. In: Cassano GB, Pancheri P, Pavan L, Pazzagli A, Ravizza L, Rossi R, and others, editors. Trattato Italiano di psichiatria. Milano (IT): Masson; 1999. p 2041–71. 50. Nisita C, Petracca A. Disturbo d’ansia generalizzato. In: Cassano GB, Pancheri P, Pavan L, Pazzagli A, Ravizza L, Rossi R, and others, editors. Trattato Italiano di psichiatria. Milano (IT): Masson; 1999. p 2099–110. Author(s)Manuscript received October 2003, revised, and accepted March 2004. 1. Researcher, Department of Neuroscience, Division of Psychiatry, University of Siena, Siena, Italy. 2. Trainee, Department of Neuroscience, Division of Psychiatry, University of Siena, Siena, Italy. 3. Professor, Department of Neuroscience, Division of Psychiatry, University of Siena, Siena, Italy. Address for correspondence: Dr L Bossini, Dipartimento di Neuroscienze, Sezione di Psichiatria c/o Policlinico “Le Scotte,” Viale Bracci, 53100, Siena, Italy e-mail: bossini2@unisi.it
1 | 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
