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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00490139




Registration number
NCT00490139
Ethics application status
Date submitted
20/06/2007
Date registered
22/06/2007
Date last updated
21/05/2019

Titles & IDs
Public title
ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D
Scientific title
A Randomised, Multi-centre, Open-label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their Combination in Patients With HER2/ErbB2 Positive Primary Breast Cancer
Secondary ID [1] 0 0
CLAP016B2301
Secondary ID [2] 0 0
EGF106708
Universal Trial Number (UTN)
Trial acronym
ALTTO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms, Breast 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Lapatinib
Other interventions - Trastuzumab

Active Comparator: Arm 1: Trastuzumab - Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks.
Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).

Experimental: Arm 2: Lapatinib - Based on the IDMC results from 18 August 2011, any patient enrolled onto Arm 2 should be considered for a new treatment strategy based on discussion with their physician.
Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks.
Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).

Experimental: Arm 3: Trastuzumab followed by Lapatinib - Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).

Experimental: Arm 4: Lapatinib in combination with Trastuzumab - Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).


Treatment: Drugs: Lapatinib
Small molecule inhibitor

Other interventions: Trastuzumab
Antibody

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Disease-free Survival (DFS) - Disease-free survival is defined as the interval between randomization and the date of the first occurence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer (SPC), or death from any cause. DFS was estimated using the Kaplan Meier method.The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years.
Timepoint [1] 0 0
From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
Secondary outcome [1] 0 0
Overall Survival (OS) - Overall survival is defined as the time from randomization until death due to any cause. Overall survival was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years.
Timepoint [1] 0 0
From randomization until death due to any cause (median follow-up of 4.5 years)
Secondary outcome [2] 0 0
Time to Recurrence - Time to recurrence is defined as the interval between the date of randomization and the date of the first occurrence of a disease recurrence (local, regional or distant). The percentile data values presented here indicate the percentage (95, 90, 85, and 80 percent) of participants who did not have disease recurrence for the indicated years. IDMC=Independent Data Monitoring Committee.
Timepoint [2] 0 0
From randomization until the date of the first occurrence of a disease recurrence (median follow-up of 4.5 years)
Secondary outcome [3] 0 0
Time to Distant Recurrence - Time to distant recurrence is defined as the interval between the date of randomization and the date of the first occurrence of distant recurrence (including central nervous system recurrence). The percentile data values presented here indicate the percentage (95, 90, 85 and 80 percent) of participants who did not have distant recurrence for the indicated years.
Timepoint [3] 0 0
From randomization until the date of the first occurrence of distant recurrence (median follow-up of 4.5 years)
Secondary outcome [4] 0 0
Time to Central Nervous System Recurrence - Time to central nervous system recurrence is defined as the time from randomization until the first central nervous system recurrence. Both brain metastasis and meningitis carcinomatosa were considered.The percentile data values presented here indicate that 95 percent of participants did not have central nervous system recurrence for the indicated years.
Timepoint [4] 0 0
From randomization until the first central nervous system recurrence (median follow-up of 4.5 years)
Secondary outcome [5] 0 0
DFS Ignoring Non-breast Second Primary Malignancies - Disease-free survival is defined as the interval between randomization and the date of the first occurence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer, or death from any cause. DFS was estimated using the Kaplan Meier method. The non-breast second primary malignancies were not considered events.The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who did not have DFS ignoring non-breast second primary malignancies for the indicated years. Zero participants were analyzed in the lapatinib arm, as the IDMC discontinued the lapatinib-alone arm due to futility at the time of the first interim analysis (lapatinib participants were then offered trastuzumab).
Timepoint [5] 0 0
From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)

Eligibility
Key inclusion criteria
- Age = 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status = 1;

- Non-metastatic operable primary invasive adenocarcinoma of the breast fulfilling the
following:

1. Histologically confirmed

2. Adequately excised (exceptions: patients who have 'non-resectable' deep margin
invasion are eligible provided they have had or will receive radiotherapy
encompassing the region concerned; patients with histologically documented
infiltration of the skin (pT4) are eligible provided they have undergone or will
receive radiotherapy encompassing the tumour bed);

3. Axilla dissected; sentinel node sampling is allowed provided that axillary
dissection follows confirmation of a positive sentinel node; sentinel node
sampling alone is NOT acceptable after neoadjuvant chemotherapy (in patients
receiving neoadjuvant chemotherapy lymph node status will be considered unknown,
regardless of the results of post-chemotherapy axillary dissection);

4. Axillary node positive patient OR node negative patient with a tumour greater
than or equal to 1.0 cm in greatest diameter. For clarification, isolated tumour
cells (ITC) are considered pN0 and micrometastases are considered pN1

- Known hormone receptor status (ER/PgR or ER alone)

- For Designs 1 and 2: Patients must have received at least four cycles of an approved
anthracycline-based (neo-) adjuvant chemotherapy regimen or listed as an exception in
Table 5 of the protocol.

For Design 1: Randomization must be performed no longer than 12 weeks from day 1 of the
last chemotherapy cycle after obtaining a post-chemotherapy LVEF = 50. Study treatment must
start no more than 14 days after randomization For Design 2: Randomization must be
performed no longer than 6 weeks from day 1 of the last anthracycline-containing
chemotherapy cycle after obtaining a post-anthracycline chemotherapy LVEF = 50. Study
treatment must start no more than 14 days after randomization and must be concurrent with
taxanes.

For Design 2B: Randomisation must be performed no longer than 8 weeks from definitive
surgery. Non-anthracycline platinum containing regimen (docetaxel and carboplatin) and
study treatment must start concomitantly and no more than 14 days after randomisation.

- Baseline LVEF =50% measured by echocardiography or MUGA scan. For Design 1 and Design
2 - after completion of all anthracycline-based (neo-) adjuvant chemotherapy and prior
to the targeted therapy(ies); for Design 2B - prior to targeted therapy(ies) and
chemotherapy (docetaxel and carboplatin)

- Over expression and/or amplification of HER2 in the invasive component of the primary
tumour (in case of neoadjuvant treatment, tissue sample used for HER2 testing should
be collected before neoadjuvant treatment starts), according to one of the following
definitions [Wolff et al 2007] and confirmed by central laboratory prior to
randomization:

- 3+ over expression by IHC (> 30% of invasive tumour cells);

- 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ
hybridization (FISH/CISH) test demonstrating HER2 gene amplification;

- HER2 gene amplification by FISH/CISH ( > 6 HER2 gene copies per nucleus, or a FISH
ratio [HER2 gene copies to chromosome 17 signals] of > than 2.2.) Patients with a
negative or equivocal overall result (FISH test ratio of = 2.2, = 6.0 HER2 gene copies
per nucleus) and staining scores of 0, 1+, 2+ or 3+ (in 30% or less neoplastic cells)
by IHC are not eligible for participation in the trial.

Equivocal local results may be submitted for a final determination by the central
laboratory.

- Completion of all necessary baseline laboratory and radiological investigations

- Signed written informed consent (approved by an Independent Ethics Committee (IEC) and
obtained prior to any study specific screening procedures).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- History of any prior (ipsi- and/or contralateral) invasive breast carcinoma;

- Past (less than 10 years) or current history of malignant neoplasms, except for
curatively treated 1) basal and squamous cell carcinoma of the skin or 2) carcinoma in
situ of the cervix.

NOTE: Patients with a prior malignancy diagnosed greater than 10 years in the past who have
been curatively treated with surgery ONLY, WITHOUT radiation therapy or systemic therapy
(chemotherapy or endocrine) are eligible for the study. Patients with any prior diagnosis
of breast cancer or melanoma, at any time, are excluded from this study.

- Any clinically staged T4 tumour, including inflammatory breast cancer;

- Bilateral tumours;

- This exclusion criterion has been removed as of protocol amendment 1.

NOTE: multifocal/multicentric tumours are permitted:

- If the patient is node-negative: one of the lesions must be equal or greater than 1.0
cm (sum of the lesion diameters is not acceptable) AND must have positive HER2 status
centrally-confirmed;

- If patient is node-positive: lesion size does not matter BUT one of the lesions must
have HER2 positivity centrally-confirmed. If several lesions are found to be HER2
positive locally, the largest lesion should be considered for central review.

- Maximum cumulative dose of doxorubicin >360mg/m² or maximum cumulative dose of
epirubicin >720mg/m² or any prior anthracyclines unrelated to the present breast
cancer;

- (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell
support;

- Any prior mediastinal irradiation except internal mammary node irradiation for the
present breast cancer;

- Patients with positive or suspicious internal mammary nodes identified by sentinel
node technique which have not been irradiated or will not be irradiated, or patients
with supraclavicular lymph node involvement (confirmed by fine needle aspirate or
biopsy);

- Prior use of anti-HER2 therapy for any reason or other prior biologic or immunotherapy
for breast cancer;

- Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the
present breast cancer;

- Concurrent anti-cancer treatment in another investigational trial with hormone therapy
or immunotherapy unless approved by the Executive Committee:

- Serious cardiac illness or medical conditions including but not confined to:

History of documented congestive heart failure (CHF) or systolic dysfunction (LVEF <50%);
High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block,
supraventricular arrhythmias which are not adequately rate-controlled); Angina pectoris
requiring antianginal medication; Clinically significant valvular heart disease; Evidence
of transmural infarction on ECG; Poorly controlled hypertension (e.g. systolic >180mm Hg or
diastolic >100mm Hg);

- Other concurrent serious diseases that may interfere with planned treatment including
severe pulmonary conditions/illness;

- Any of the following abnormal laboratory tests immediately prior to randomization:

serum total bilirubin >1.5 x upper limit of normal (ULN), in the case of known Gilbert's
syndrome, a higher serum total bilirubin (<2 X ULN) is allowed; alanine amino transferase
(ALAT) or aspartate amino transferase (ASAT) >2.5 x ULN; alkaline phosphatase (ALP) > 2.5 x
ULN; serum creatinine >2.0 x ULN; total white blood cell count (WBC) <2.5 x 10^9/L;
absolute neutrophil count <1.5 x 10^9/L; platelets <100 x 10^9/L.

- Unresolved or unstable serious adverse events from prior adjuvant chemotherapy or
radiotherapy;

- Malabsorption syndrome, any disease significantly affecting gastrointestinal function,
or resection of the stomach or small bowel, or persons unable to swallow oral
medication. Subjects with ulcerative colitis are also excluded;

- Pregnant, lactating or women of childbearing potential without a negative pregnancy
test - urine or serum - within 7 days prior to randomization, irrespective of the
method of contraception used, including tubal ligation;

- Women of childbearing potential and male participants with partners of child bearing
potential, including women whose last menstrual period was <12 months ago (unless
surgically sterile) who are unable or unwilling to use adequate contraceptive measures
during study treatment (adequate contraceptive measures: intra-uterine device, barrier
method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total
abstinence. Oral, injectable, or implant hormonal contraceptives are not indicated in
this patient population);

- Concomitant use of CYP3A4 inhibitors or inducers.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC,WA
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Novartis Investigative Site - Camperdown
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Novartis Investigative Site - East Bentleigh
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Novartis Investigative Site - East Melbourne
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Novartis Investigative Site - Heidelberg
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Novartis Investigative Site - Melbourne
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Novartis Investigative Site - Parkville
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Novartis Investigative Site - Ringwood East
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Novartis Investigative Site - Wendouree
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Novartis Investigative Site - Bunbury
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Novartis Investigative Site - Nedlands
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Novartis Investigative Site - Lismore
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Novartis Investigative Site - Murdoch
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
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2450 - Coffs Harbour
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2139 - Concord
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2747 - Kingswood
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2170 - Liverpool
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2060 - North Sydney
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2444 - Port Macquarie
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2031 - Randwick
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2430 - Taree
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2485 - Tweed Heads
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2650 - Wagga Wagga
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2298 - Waratah
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2145 - Westmead
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4560 - Nambour
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4101 - South Brisbane
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4102 - Woolloongabba
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5000 - Adelaide
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5042 - Bedford Park
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5011 - Woodville
Recruitment postcode(s) [20] 0 0
7000 - Hobart
Recruitment postcode(s) [21] 0 0
3128 - Box Hill
Recruitment postcode(s) [22] 0 0
3165 - East Bentleigh
Recruitment postcode(s) [23] 0 0
3002 - East Melbourne
Recruitment postcode(s) [24] 0 0
3065 - Fitzroy
Recruitment postcode(s) [25] 0 0
3011 - Footscray
Recruitment postcode(s) [26] 0 0
3199 - Frankston
Recruitment postcode(s) [27] 0 0
3084 - Heidelberg
Recruitment postcode(s) [28] 0 0
3002 - Melbourne
Recruitment postcode(s) [29] 0 0
3050 - Parkville
Recruitment postcode(s) [30] 0 0
3135 - Ringwood East
Recruitment postcode(s) [31] 0 0
3355 - Wendouree
Recruitment postcode(s) [32] 0 0
6230 - Bunbury
Recruitment postcode(s) [33] 0 0
6009 - Nedlands
Recruitment postcode(s) [34] 0 0
6008 - Subiaco
Recruitment postcode(s) [35] 0 0
2560 - Campbelltown
Recruitment postcode(s) [36] 0 0
2480 - Lismore
Recruitment postcode(s) [37] 0 0
6150 - Murdoch
Recruitment outside Australia
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Wyoming
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Argentina
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Santa Fe
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Ciudad Autonoma de Buenos Aires
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Mendoza
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Quilmes
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Tucuman
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Austria
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Guessing
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Linz
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Rankweil
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Salzburg
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Steyr
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Vienna
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Villach
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Wien
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Wolfsberg
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Country [68] 0 0
Belgium
State/province [68] 0 0
Antwerpen
Country [69] 0 0
Belgium
State/province [69] 0 0
Bonheiden
Country [70] 0 0
Belgium
State/province [70] 0 0
Brasschaat
Country [71] 0 0
Belgium
State/province [71] 0 0
Brugge
Country [72] 0 0
Belgium
State/province [72] 0 0
Brussels
Country [73] 0 0
Belgium
State/province [73] 0 0
Brussel
Country [74] 0 0
Belgium
State/province [74] 0 0
Bruxelles
Country [75] 0 0
Belgium
State/province [75] 0 0
Charleroi
Country [76] 0 0
Belgium
State/province [76] 0 0
Edegem
Country [77] 0 0
Belgium
State/province [77] 0 0
Genk
Country [78] 0 0
Belgium
State/province [78] 0 0
Gent
Country [79] 0 0
Belgium
State/province [79] 0 0
Haine Saint Paul
Country [80] 0 0
Belgium
State/province [80] 0 0
Hasselt
Country [81] 0 0
Belgium
State/province [81] 0 0
Huy
Country [82] 0 0
Belgium
State/province [82] 0 0
Kortrijk
Country [83] 0 0
Belgium
State/province [83] 0 0
Leuven
Country [84] 0 0
Belgium
State/province [84] 0 0
Liege
Country [85] 0 0
Belgium
State/province [85] 0 0
Mons
Country [86] 0 0
Belgium
State/province [86] 0 0
Namur
Country [87] 0 0
Belgium
State/province [87] 0 0
Roeselare
Country [88] 0 0
Belgium
State/province [88] 0 0
Sint-Niklaas
Country [89] 0 0
Belgium
State/province [89] 0 0
Tournai
Country [90] 0 0
Belgium
State/province [90] 0 0
Turnhout
Country [91] 0 0
Belgium
State/province [91] 0 0
Verviers
Country [92] 0 0
Belgium
State/province [92] 0 0
Wilrijk
Country [93] 0 0
Belgium
State/province [93] 0 0
Yvoir
Country [94] 0 0
Brazil
State/province [94] 0 0
Bahía
Country [95] 0 0
Brazil
State/province [95] 0 0
Minas Gerais
Country [96] 0 0
Brazil
State/province [96] 0 0
Rio Grande Do Sul
Country [97] 0 0
Brazil
State/province [97] 0 0
São Paulo
Country [98] 0 0
Brazil
State/province [98] 0 0
Rio de Janeiro
Country [99] 0 0
Bulgaria
State/province [99] 0 0
Shumen
Country [100] 0 0
Bulgaria
State/province [100] 0 0
Sofia
Country [101] 0 0
Bulgaria
State/province [101] 0 0
Varna
Country [102] 0 0
Canada
State/province [102] 0 0
British Columbia
Country [103] 0 0
Canada
State/province [103] 0 0
New Brunswick
Country [104] 0 0
Canada
State/province [104] 0 0
Ontario
Country [105] 0 0
Canada
State/province [105] 0 0
Prince Edward Island
Country [106] 0 0
Canada
State/province [106] 0 0
Quebec
Country [107] 0 0
Canada
State/province [107] 0 0
Saskatchewan
Country [108] 0 0
Chile
State/province [108] 0 0
Región De La Araucania
Country [109] 0 0
Chile
State/province [109] 0 0
Región De Los Lagos
Country [110] 0 0
Chile
State/province [110] 0 0
Región Metro De Santiago
Country [111] 0 0
Chile
State/province [111] 0 0
Valparaíso
Country [112] 0 0
Chile
State/province [112] 0 0
Arica
Country [113] 0 0
China
State/province [113] 0 0
Guangdong
Country [114] 0 0
China
State/province [114] 0 0
Beijing
Country [115] 0 0
China
State/province [115] 0 0
Shanghai
Country [116] 0 0
China
State/province [116] 0 0
Tianjin
Country [117] 0 0
Croatia
State/province [117] 0 0
Varazdin
Country [118] 0 0
Croatia
State/province [118] 0 0
Zagreb
Country [119] 0 0
Czechia
State/province [119] 0 0
Brno
Country [120] 0 0
Czechia
State/province [120] 0 0
Ceske Budejovice
Country [121] 0 0
Czechia
State/province [121] 0 0
Chomutov
Country [122] 0 0
Czechia
State/province [122] 0 0
Jihlava
Country [123] 0 0
Czechia
State/province [123] 0 0
Novy Jicin
Country [124] 0 0
Czechia
State/province [124] 0 0
Olomouc
Country [125] 0 0
Czechia
State/province [125] 0 0
Pardubice
Country [126] 0 0
Czechia
State/province [126] 0 0
Praha 10
Country [127] 0 0
Czechia
State/province [127] 0 0
Praha 2
Country [128] 0 0
Czechia
State/province [128] 0 0
Praha 4
Country [129] 0 0
Czechia
State/province [129] 0 0
Praha 5
Country [130] 0 0
Czechia
State/province [130] 0 0
Praha 8
Country [131] 0 0
Czechia
State/province [131] 0 0
Usti nad Labem
Country [132] 0 0
Denmark
State/province [132] 0 0
Aalborg
Country [133] 0 0
Denmark
State/province [133] 0 0
Arhus C
Country [134] 0 0
Denmark
State/province [134] 0 0
Esbjerg
Country [135] 0 0
Denmark
State/province [135] 0 0
Herlev
Country [136] 0 0
Denmark
State/province [136] 0 0
Hilleroed
Country [137] 0 0
Denmark
State/province [137] 0 0
Koebenhavn Oe
Country [138] 0 0
Denmark
State/province [138] 0 0
Naestved
Country [139] 0 0
Denmark
State/province [139] 0 0
Odense
Country [140] 0 0
Denmark
State/province [140] 0 0
Roskilde
Country [141] 0 0
Denmark
State/province [141] 0 0
Vejle
Country [142] 0 0
Denmark
State/province [142] 0 0
Viborg
Country [143] 0 0
Estonia
State/province [143] 0 0
Tallinn
Country [144] 0 0
Estonia
State/province [144] 0 0
Tartu
Country [145] 0 0
France
State/province [145] 0 0
ANGERS Cedex 2
Country [146] 0 0
France
State/province [146] 0 0
Annecy
Country [147] 0 0
France
State/province [147] 0 0
Avignon
Country [148] 0 0
France
State/province [148] 0 0
Bayonne
Country [149] 0 0
France
State/province [149] 0 0
Bethune
Country [150] 0 0
France
State/province [150] 0 0
Bordeaux
Country [151] 0 0
France
State/province [151] 0 0
Brive La Gaillarde
Country [152] 0 0
France
State/province [152] 0 0
Bron
Country [153] 0 0
France
State/province [153] 0 0
Caen Cedex 05
Country [154] 0 0
France
State/province [154] 0 0
Caen
Country [155] 0 0
France
State/province [155] 0 0
Clermont Ferrand
Country [156] 0 0
France
State/province [156] 0 0
Coudekerque Branche
Country [157] 0 0
France
State/province [157] 0 0
Dijon Cedex
Country [158] 0 0
France
State/province [158] 0 0
Dijon
Country [159] 0 0
France
State/province [159] 0 0
Draguignan
Country [160] 0 0
France
State/province [160] 0 0
Grenoble Cedex 9
Country [161] 0 0
France
State/province [161] 0 0
Grenoble Cedex
Country [162] 0 0
France
State/province [162] 0 0
Hyeres
Country [163] 0 0
France
State/province [163] 0 0
La Seyne Sur Mer
Country [164] 0 0
France
State/province [164] 0 0
Le Chesnay
Country [165] 0 0
France
State/province [165] 0 0
Le Havre
Country [166] 0 0
France
State/province [166] 0 0
Le Mans
Country [167] 0 0
France
State/province [167] 0 0
Lille
Country [168] 0 0
France
State/province [168] 0 0
Lyon
Country [169] 0 0
France
State/province [169] 0 0
Marseille Cedex 09
Country [170] 0 0
France
State/province [170] 0 0
Marseille cedex 5
Country [171] 0 0
France
State/province [171] 0 0
Marseille
Country [172] 0 0
France
State/province [172] 0 0
Metz cedex 01
Country [173] 0 0
France
State/province [173] 0 0
Mont de Marsan
Country [174] 0 0
France
State/province [174] 0 0
Montauban
Country [175] 0 0
France
State/province [175] 0 0
Montbeliard
Country [176] 0 0
France
State/province [176] 0 0
Mulhouse
Country [177] 0 0
France
State/province [177] 0 0
Nancy
Country [178] 0 0
France
State/province [178] 0 0
Nice Cedex 2
Country [179] 0 0
France
State/province [179] 0 0
Nimes cedex 9
Country [180] 0 0
France
State/province [180] 0 0
Paris Cedex 10
Country [181] 0 0
France
State/province [181] 0 0
Paris Cedex 14
Country [182] 0 0
France
State/province [182] 0 0
Paris Cedex 5
Country [183] 0 0
France
State/province [183] 0 0
Perigueux
Country [184] 0 0
France
State/province [184] 0 0
Perin Sur Mer
Country [185] 0 0
France
State/province [185] 0 0
Perpignan
Country [186] 0 0
France
State/province [186] 0 0
Reims
Country [187] 0 0
France
State/province [187] 0 0
Rouen cedex 1
Country [188] 0 0
France
State/province [188] 0 0
Rouen
Country [189] 0 0
France
State/province [189] 0 0
Saint Gregoire
Country [190] 0 0
France
State/province [190] 0 0
Saint Jean
Country [191] 0 0
France
State/province [191] 0 0
Saint-Cloud
Country [192] 0 0
France
State/province [192] 0 0
Saint-Herblain
Country [193] 0 0
France
State/province [193] 0 0
Saint-Martin Boulogne
Country [194] 0 0
France
State/province [194] 0 0
Saint-Priest en Jarez Cedex
Country [195] 0 0
France
State/province [195] 0 0
Strasbourg
Country [196] 0 0
France
State/province [196] 0 0
Toulouse
Country [197] 0 0
France
State/province [197] 0 0
Tours cedex
Country [198] 0 0
France
State/province [198] 0 0
Valenciennes
Country [199] 0 0
France
State/province [199] 0 0
Vandoeuvre-Les-Nancy
Country [200] 0 0
France
State/province [200] 0 0
Villejuif Cedex
Country [201] 0 0
Germany
State/province [201] 0 0
Baden-Wuerttemberg
Country [202] 0 0
Germany
State/province [202] 0 0
Bayern
Country [203] 0 0
Germany
State/province [203] 0 0
Brandenburg
Country [204] 0 0
Germany
State/province [204] 0 0
Bremen
Country [205] 0 0
Germany
State/province [205] 0 0
Hessen
Country [206] 0 0
Germany
State/province [206] 0 0
Mecklenburg-Vorpommern
Country [207] 0 0
Germany
State/province [207] 0 0
Niedersachsen
Country [208] 0 0
Germany
State/province [208] 0 0
Nordrhein-Westfalen
Country [209] 0 0
Germany
State/province [209] 0 0
Rheinland-Pfalz
Country [210] 0 0
Germany
State/province [210] 0 0
Saarland
Country [211] 0 0
Germany
State/province [211] 0 0
Sachsen-Anhalt
Country [212] 0 0
Germany
State/province [212] 0 0
Sachsen
Country [213] 0 0
Germany
State/province [213] 0 0
Schleswig-Holstein
Country [214] 0 0
Germany
State/province [214] 0 0
Thueringen
Country [215] 0 0
Germany
State/province [215] 0 0
Berlin
Country [216] 0 0
Germany
State/province [216] 0 0
Friedrichshafen
Country [217] 0 0
Germany
State/province [217] 0 0
Hamburg
Country [218] 0 0
Germany
State/province [218] 0 0
Wuerzburg
Country [219] 0 0
Greece
State/province [219] 0 0
Athens
Country [220] 0 0
Greece
State/province [220] 0 0
Heraklion,Crete
Country [221] 0 0
Greece
State/province [221] 0 0
Patra
Country [222] 0 0
Greece
State/province [222] 0 0
Thessaloniki
Country [223] 0 0
Hong Kong
State/province [223] 0 0
Kowloon
Country [224] 0 0
Hong Kong
State/province [224] 0 0
Tuen Mun
Country [225] 0 0
Hungary
State/province [225] 0 0
Budapest
Country [226] 0 0
Hungary
State/province [226] 0 0
Gyor
Country [227] 0 0
Hungary
State/province [227] 0 0
Szeged
Country [228] 0 0
Hungary
State/province [228] 0 0
Szombathely
Country [229] 0 0
India
State/province [229] 0 0
Gurgaon
Country [230] 0 0
India
State/province [230] 0 0
Hyderabad
Country [231] 0 0
India
State/province [231] 0 0
Kolkatta (w.b.)
Country [232] 0 0
India
State/province [232] 0 0
Mangalore
Country [233] 0 0
India
State/province [233] 0 0
Mumbai
Country [234] 0 0
India
State/province [234] 0 0
Nagpur
Country [235] 0 0
India
State/province [235] 0 0
New Delhi
Country [236] 0 0
India
State/province [236] 0 0
Trivandrum
Country [237] 0 0
Ireland
State/province [237] 0 0
Dublin
Country [238] 0 0
Ireland
State/province [238] 0 0
Galway
Country [239] 0 0
Ireland
State/province [239] 0 0
Limerick
Country [240] 0 0
Ireland
State/province [240] 0 0
Sligo
Country [241] 0 0
Ireland
State/province [241] 0 0
Tallaght, Dublin
Country [242] 0 0
Ireland
State/province [242] 0 0
Wilton, Cork
Country [243] 0 0
Israel
State/province [243] 0 0
Beer-Sheva
Country [244] 0 0
Israel
State/province [244] 0 0
Haifa
Country [245] 0 0
Israel
State/province [245] 0 0
Holon
Country [246] 0 0
Israel
State/province [246] 0 0
Jerusalem
Country [247] 0 0
Israel
State/province [247] 0 0
Kfar Saba
Country [248] 0 0
Israel
State/province [248] 0 0
Netanya
Country [249] 0 0
Israel
State/province [249] 0 0
Ramat Gan
Country [250] 0 0
Israel
State/province [250] 0 0
Rehovot
Country [251] 0 0
Israel
State/province [251] 0 0
Tel Aviv
Country [252] 0 0
Italy
State/province [252] 0 0
Basilicata
Country [253] 0 0
Italy
State/province [253] 0 0
Campania
Country [254] 0 0
Italy
State/province [254] 0 0
Emilia-Romagna
Country [255] 0 0
Italy
State/province [255] 0 0
Friuli-Venezia-Giulia
Country [256] 0 0
Italy
State/province [256] 0 0
Lazio
Country [257] 0 0
Italy
State/province [257] 0 0
Liguria
Country [258] 0 0
Italy
State/province [258] 0 0
Lombardia
Country [259] 0 0
Italy
State/province [259] 0 0
Marche
Country [260] 0 0
Italy
State/province [260] 0 0
Piemonte
Country [261] 0 0
Italy
State/province [261] 0 0
Puglia
Country [262] 0 0
Italy
State/province [262] 0 0
Sardegna
Country [263] 0 0
Italy
State/province [263] 0 0
Sicilia
Country [264] 0 0
Italy
State/province [264] 0 0
Toscana
Country [265] 0 0
Italy
State/province [265] 0 0
Trentino-Alto Adige
Country [266] 0 0
Italy
State/province [266] 0 0
Chieti
Country [267] 0 0
Italy
State/province [267] 0 0
Cosenza
Country [268] 0 0
Japan
State/province [268] 0 0
Aichi
Country [269] 0 0
Japan
State/province [269] 0 0
Chiba
Country [270] 0 0
Japan
State/province [270] 0 0
Ehime
Country [271] 0 0
Japan
State/province [271] 0 0
Fukuoka
Country [272] 0 0
Japan
State/province [272] 0 0
Ibaraki
Country [273] 0 0
Japan
State/province [273] 0 0
Kanagawa
Country [274] 0 0
Japan
State/province [274] 0 0
Kyoto
Country [275] 0 0
Japan
State/province [275] 0 0
Osaka
Country [276] 0 0
Japan
State/province [276] 0 0
Saitama
Country [277] 0 0
Japan
State/province [277] 0 0
Tokyo
Country [278] 0 0
Korea, Republic of
State/province [278] 0 0
Gyeonggi-do
Country [279] 0 0
Korea, Republic of
State/province [279] 0 0
Incheon
Country [280] 0 0
Korea, Republic of
State/province [280] 0 0
Seoul
Country [281] 0 0
Korea, Republic of
State/province [281] 0 0
Suwon-si, Gyeonggi-do
Country [282] 0 0
Malaysia
State/province [282] 0 0
Kubang Kerian
Country [283] 0 0
Malaysia
State/province [283] 0 0
Sarawak
Country [284] 0 0
Mexico
State/province [284] 0 0
Estado De México
Country [285] 0 0
Mexico
State/province [285] 0 0
Yucatán
Country [286] 0 0
Mexico
State/province [286] 0 0
Chihuahua
Country [287] 0 0
Mexico
State/province [287] 0 0
Mexico City
Country [288] 0 0
Mexico
State/province [288] 0 0
Mexico D.F.
Country [289] 0 0
Mexico
State/province [289] 0 0
Mexico DF
Country [290] 0 0
Netherlands
State/province [290] 0 0
Amersfoort
Country [291] 0 0
Netherlands
State/province [291] 0 0
Amsterdam
Country [292] 0 0
Netherlands
State/province [292] 0 0
Arnhem
Country [293] 0 0
Netherlands
State/province [293] 0 0
Blaricum
Country [294] 0 0
Netherlands
State/province [294] 0 0
Delft
Country [295] 0 0
Netherlands
State/province [295] 0 0
Den Haag
Country [296] 0 0
Netherlands
State/province [296] 0 0
Eindhoven
Country [297] 0 0
Netherlands
State/province [297] 0 0
Gouda
Country [298] 0 0
Netherlands
State/province [298] 0 0
Hoofddorp
Country [299] 0 0
Netherlands
State/province [299] 0 0
Leeuwarden
Country [300] 0 0
Netherlands
State/province [300] 0 0
Leiden
Country [301] 0 0
Netherlands
State/province [301] 0 0
Leidschendam
Country [302] 0 0
Netherlands
State/province [302] 0 0
Purmerend
Country [303] 0 0
Netherlands
State/province [303] 0 0
Rotterdam
Country [304] 0 0
Netherlands
State/province [304] 0 0
Sittard-geleen
Country [305] 0 0
Netherlands
State/province [305] 0 0
Tilburg
Country [306] 0 0
Netherlands
State/province [306] 0 0
Utrecht
Country [307] 0 0
New Zealand
State/province [307] 0 0
Hamilton
Country [308] 0 0
New Zealand
State/province [308] 0 0
Palmerston North
Country [309] 0 0
New Zealand
State/province [309] 0 0
Wellington
Country [310] 0 0
Norway
State/province [310] 0 0
Forde
Country [311] 0 0
Norway
State/province [311] 0 0
Oslo
Country [312] 0 0
Norway
State/province [312] 0 0
Tromso
Country [313] 0 0
Pakistan
State/province [313] 0 0
Karachi
Country [314] 0 0
Pakistan
State/province [314] 0 0
Lahore
Country [315] 0 0
Pakistan
State/province [315] 0 0
Rawalpindi
Country [316] 0 0
Peru
State/province [316] 0 0
Callao
Country [317] 0 0
Peru
State/province [317] 0 0
Lima
Country [318] 0 0
Philippines
State/province [318] 0 0
Cebu
Country [319] 0 0
Philippines
State/province [319] 0 0
Quezon City
Country [320] 0 0
Philippines
State/province [320] 0 0
Sampaloc Manila
Country [321] 0 0
Philippines
State/province [321] 0 0
San Juan
Country [322] 0 0
Poland
State/province [322] 0 0
Bydgoszcz
Country [323] 0 0
Poland
State/province [323] 0 0
Elblag
Country [324] 0 0
Poland
State/province [324] 0 0
Gdansk
Country [325] 0 0
Poland
State/province [325] 0 0
Gliwice
Country [326] 0 0
Poland
State/province [326] 0 0
Krakow
Country [327] 0 0
Poland
State/province [327] 0 0
Olsztyn
Country [328] 0 0
Poland
State/province [328] 0 0
Opole
Country [329] 0 0
Poland
State/province [329] 0 0
Rzeszow
Country [330] 0 0
Poland
State/province [330] 0 0
Szczecin
Country [331] 0 0
Poland
State/province [331] 0 0
Warszawa
Country [332] 0 0
Poland
State/province [332] 0 0
Wroclaw
Country [333] 0 0
Romania
State/province [333] 0 0
Bucharest
Country [334] 0 0
Romania
State/province [334] 0 0
Bucuresti
Country [335] 0 0
Romania
State/province [335] 0 0
Cluj-Napoca
Country [336] 0 0
Romania
State/province [336] 0 0
Iasi
Country [337] 0 0
Russian Federation
State/province [337] 0 0
Arkhangelsk
Country [338] 0 0
Russian Federation
State/province [338] 0 0
Chelyabinsk
Country [339] 0 0
Russian Federation
State/province [339] 0 0
Irkutsk
Country [340] 0 0
Russian Federation
State/province [340] 0 0
Kazan
Country [341] 0 0
Russian Federation
State/province [341] 0 0
Kirov
Country [342] 0 0
Russian Federation
State/province [342] 0 0
Moscow
Country [343] 0 0
Russian Federation
State/province [343] 0 0
Novosibirsk
Country [344] 0 0
Russian Federation
State/province [344] 0 0
Omsk
Country [345] 0 0
Russian Federation
State/province [345] 0 0
Orenburg
Country [346] 0 0
Russian Federation
State/province [346] 0 0
Ryazan
Country [347] 0 0
Russian Federation
State/province [347] 0 0
Samara
Country [348] 0 0
Russian Federation
State/province [348] 0 0
St. Petersburg
Country [349] 0 0
Russian Federation
State/province [349] 0 0
Voronezh
Country [350] 0 0
Singapore
State/province [350] 0 0
Singapore
Country [351] 0 0
Slovakia
State/province [351] 0 0
Bratislava
Country [352] 0 0
Slovakia
State/province [352] 0 0
Kosice
Country [353] 0 0
Slovakia
State/province [353] 0 0
Poprad
Country [354] 0 0
Slovakia
State/province [354] 0 0
Rimavska Sobota
Country [355] 0 0
Slovakia
State/province [355] 0 0
Zilina
Country [356] 0 0
Slovenia
State/province [356] 0 0
Ljubljana
Country [357] 0 0
South Africa
State/province [357] 0 0
Capital Park
Country [358] 0 0
South Africa
State/province [358] 0 0
Groenkloof, Pretoria, 0001
Country [359] 0 0
South Africa
State/province [359] 0 0
Johannesburg
Country [360] 0 0
South Africa
State/province [360] 0 0
Observatory
Country [361] 0 0
South Africa
State/province [361] 0 0
Panorama
Country [362] 0 0
South Africa
State/province [362] 0 0
Parktown
Country [363] 0 0
South Africa
State/province [363] 0 0
Pretoria
Country [364] 0 0
South Africa
State/province [364] 0 0
Saxonwold, Johannesburg
Country [365] 0 0
Spain
State/province [365] 0 0
Alcoy/Alicante
Country [366] 0 0
Spain
State/province [366] 0 0
Barakaldo (Vizcaya)
Country [367] 0 0
Spain
State/province [367] 0 0
Barcelona
Country [368] 0 0
Spain
State/province [368] 0 0
Burgos
Country [369] 0 0
Spain
State/province [369] 0 0
Cadiz
Country [370] 0 0
Spain
State/province [370] 0 0
Castellon
Country [371] 0 0
Spain
State/province [371] 0 0
Cordoba
Country [372] 0 0
Spain
State/province [372] 0 0
Coria
Country [373] 0 0
Spain
State/province [373] 0 0
Elda
Country [374] 0 0
Spain
State/province [374] 0 0
Granada
Country [375] 0 0
Spain
State/province [375] 0 0
Hospitalet de Llobregat (Barcelona)
Country [376] 0 0
Spain
State/province [376] 0 0
Huesca
Country [377] 0 0
Spain
State/province [377] 0 0
La Laguna (Santa Cruz De Tenerife)
Country [378] 0 0
Spain
State/province [378] 0 0
Lerida
Country [379] 0 0
Spain
State/province [379] 0 0
Lugo
Country [380] 0 0
Spain
State/province [380] 0 0
Madrid
Country [381] 0 0
Spain
State/province [381] 0 0
Malaga
Country [382] 0 0
Spain
State/province [382] 0 0
Mataro
Country [383] 0 0
Spain
State/province [383] 0 0
Mostoles (Madrid)
Country [384] 0 0
Spain
State/province [384] 0 0
Murcia
Country [385] 0 0
Spain
State/province [385] 0 0
Palma de Mallorca
Country [386] 0 0
Spain
State/province [386] 0 0
Pamplona
Country [387] 0 0
Spain
State/province [387] 0 0
Salamanca
Country [388] 0 0
Spain
State/province [388] 0 0
San Sebastian
Country [389] 0 0
Spain
State/province [389] 0 0
Santander
Country [390] 0 0
Spain
State/province [390] 0 0
Santiago
Country [391] 0 0
Spain
State/province [391] 0 0
Segovia
Country [392] 0 0
Spain
State/province [392] 0 0
Sevilla
Country [393] 0 0
Spain
State/province [393] 0 0
Tarrasa, Barcelona
Country [394] 0 0
Spain
State/province [394] 0 0
Toledo
Country [395] 0 0
Spain
State/province [395] 0 0
Valencia
Country [396] 0 0
Spain
State/province [396] 0 0
Zamora
Country [397] 0 0
Spain
State/province [397] 0 0
Zaragoza
Country [398] 0 0
Switzerland
State/province [398] 0 0
Aarau
Country [399] 0 0
Switzerland
State/province [399] 0 0
Basel
Country [400] 0 0
Switzerland
State/province [400] 0 0
Bellinzona
Country [401] 0 0
Switzerland
State/province [401] 0 0
Bern
Country [402] 0 0
Switzerland
State/province [402] 0 0
Chur
Country [403] 0 0
Switzerland
State/province [403] 0 0
Lausanne
Country [404] 0 0
Switzerland
State/province [404] 0 0
Locarno
Country [405] 0 0
Switzerland
State/province [405] 0 0
St Gallen
Country [406] 0 0
Switzerland
State/province [406] 0 0
Thun
Country [407] 0 0
Switzerland
State/province [407] 0 0
Zuerich
Country [408] 0 0
Switzerland
State/province [408] 0 0
Zurich
Country [409] 0 0
Taiwan
State/province [409] 0 0
Kaohsiung
Country [410] 0 0
Taiwan
State/province [410] 0 0
Taichung
Country [411] 0 0
Taiwan
State/province [411] 0 0
Tainan County
Country [412] 0 0
Taiwan
State/province [412] 0 0
Taipei
Country [413] 0 0
Thailand
State/province [413] 0 0
Bangkok
Country [414] 0 0
Thailand
State/province [414] 0 0
Chiangmai
Country [415] 0 0
Thailand
State/province [415] 0 0
Hatyai, Songkhla
Country [416] 0 0
Thailand
State/province [416] 0 0
Khon Kaen
Country [417] 0 0
Thailand
State/province [417] 0 0
Phitsanulok
Country [418] 0 0
Ukraine
State/province [418] 0